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| BabyScreen+ newborn screening v1.114 | PQBP1 | Tommy Li Added phenotypes Renpenning syndrome, MIM#309500 for gene: PQBP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | NIN | Tommy Li Added phenotypes Seckel syndrome for gene: NIN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | MAT1A | Tommy Li Added phenotypes Methionine adenosyltransferase deficiency MIM#250850 for gene: MAT1A | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | IRS1 | Tommy Li Added phenotypes Diabetes mellitus, noninsulin dependent for gene: IRS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | APRT | Tommy Li Added phenotypes Adenine phosphoribosyltransferase deficiency, MIM# 614723 for gene: APRT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | ADK |
Tommy Li Added phenotypes Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300 for gene: ADK Publications for gene ADK were updated from 21963049; 17120046; 33309011 to 33309011; 21963049; 17120046 |
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| BabyScreen+ newborn screening v1.114 | PTS | Tommy Li Added phenotypes Hyperphenylalaninemia, BH4-deficient, A, MIM#261640 for gene: PTS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | PCBD1 | Tommy Li Added phenotypes Hyperphenylalaninemia, BH4-deficient, D, MIM# 264070 for gene: PCBD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | GCH1 | Tommy Li Added phenotypes Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230 for gene: GCH1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | FLAD1 | Tommy Li Added phenotypes Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency, MIM# 255100 for gene: FLAD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | DNAJC12 | Tommy Li Added phenotypes Hyperphenylalaninemia, mild, non-BH4-deficient, MIM#617384 for gene: DNAJC12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | ASL | Tommy Li Added phenotypes Argininosuccinic aciduria, MIM#207900 for gene: ASL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.114 | AHCY | Tommy Li Added phenotypes Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM# 613752 for gene: AHCY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.103 | TRIM28 |
Zornitza Stark gene: TRIM28 was added gene: TRIM28 was added to BabyScreen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRIM28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRIM28 were set to 30694527 Phenotypes for gene: TRIM28 were set to Wilms tumour, MONDO:0006058, TRIM28-related Review for gene: TRIM28 was set to GREEN Added comment: Established gene-disease association, more than 10 individuals reported. Onset in childhood. Included for completeness as managed similarly to WT1. Sources: Expert list |
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| BabyScreen+ newborn screening v1.89 | REST |
Zornitza Stark gene: REST was added gene: REST was added to BabyScreen+ newborn screening. Sources: Expert list cancer, treatable tags were added to gene: REST. Mode of inheritance for gene: REST was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: REST were set to 26551668; 34308104 Phenotypes for gene: REST were set to {Wilms tumor 6, susceptibility to}, MIM# 616806 Review for gene: REST was set to GREEN Added comment: Established association, more than 10 families reported. Childhood onset. Included for completeness as managed similarly to WT1. Sources: Expert list |
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| BabyScreen+ newborn screening v1.87 | PSTPIP1 |
Zornitza Stark gene: PSTPIP1 was added gene: PSTPIP1 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: PSTPIP1. Mode of inheritance for gene: PSTPIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PSTPIP1 were set to Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416 Review for gene: PSTPIP1 was set to GREEN Added comment: Established gene-disease association. Onset in childhood. Treatment: adalimumab and tacrolimus, NSAIDs, corticosteroids, BMT non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v1.80 | POLE |
Zornitza Stark gene: POLE was added gene: POLE was added to BabyScreen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: POLE. Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POLE were set to IMAGE-I syndrome, MIM# 618336 Review for gene: POLE was set to GREEN Added comment: Established gene-disease association. Multi-system disorder comprising GH and adrenal hypoplasia. Treatment: hydrocortisone non-genetic confirmatory testing: hormone levels Sources: Expert list |
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| BabyScreen+ newborn screening v1.76 | LPL |
Zornitza Stark gene: LPL was added gene: LPL was added to BabyScreen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: LPL. Mode of inheritance for gene: LPL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LPL were set to Lipoprotein lipase deficiency, MIM# 238600 Review for gene: LPL was set to GREEN Added comment: Established gene-disease association. Bi-allelic disease is severe and presents in infancy. Treatment: volanesorsen, dietary fat restriction, lomitapide Non-genetic confirmatory testing: LPL activity Sources: Expert list |
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| BabyScreen+ newborn screening v1.74 | LAT |
Zornitza Stark gene: LAT was added gene: LAT was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: LAT. Mode of inheritance for gene: LAT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LAT were set to Immunodeficiency 52, MIM# 617514 Review for gene: LAT was set to GREEN Added comment: Established gene-disease association. SCID-like presentation. Treatment: BMT Non-genetic confirmatory testing: yes Sources: Expert list |
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| BabyScreen+ newborn screening v1.72 | KLHL3 |
Zornitza Stark gene: KLHL3 was added gene: KLHL3 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: KLHL3. Mode of inheritance for gene: KLHL3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: KLHL3 were set to Pseudohypoaldosteronism, type IID, MIM# 614495 Review for gene: KLHL3 was set to GREEN Added comment: Established gene disease association. Results in hyperkalaemia and later, the development of hypertension. Treatment: thiazide diuretics normalise electrolytes Non-genetic confirmatory testing: electrolytes Sources: Expert list |
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| BabyScreen+ newborn screening v1.70 | IRF8 |
Zornitza Stark gene: IRF8 was added gene: IRF8 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IRF8. Mode of inheritance for gene: IRF8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IRF8 were set to Immunodeficiency 32B, monocyte and dendritic cell deficiency, autosomal recessive, MIM# 226990 Review for gene: IRF8 was set to GREEN Added comment: At least 4 families reported with bi-allelic variants. Gene-disease association also proposed for mono-allelic variants but only two individuals reported. Recurrent infections presenting in infancy. Treatment: BMT Non-genetic confirmatory testing available Sources: Expert list |
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| BabyScreen+ newborn screening v1.66 | IL10 |
Zornitza Stark gene: IL10 was added gene: IL10 was added to BabyScreen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IL10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL10 were set to 22236434; 20951137; 19890111 Phenotypes for gene: IL10 were set to Autoinflammatory syndrome, MONDO:0019751, IL10-related Review for gene: IL10 was set to GREEN Added comment: Established gene-disease association. Onset in infancy and childhood. Treatment: BMT Non-genetic confirmatory testing: flow cytometry Sources: Expert list |
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| BabyScreen+ newborn screening v1.62 | GALNT3 |
Zornitza Stark gene: GALNT3 was added gene: GALNT3 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: GALNT3. Mode of inheritance for gene: GALNT3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GALNT3 were set to Tumoral calcinosis, hyperphosphatemic, familial, 1, MIM# 211900 Review for gene: GALNT3 was set to GREEN Added comment: Established gene-disease association. Onset in infancy/childhood. Treatment: dietary restriction, phosphate binders, acetazolamide Non-genetic confirmatory testing: serum phosphate, calcium, PTH, alkaline phosphatase, vitamin D serum levels, urine calcium, phosphate levels, plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 Sources: Expert list |
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| BabyScreen+ newborn screening v1.60 | FECH |
Zornitza Stark gene: FECH was added gene: FECH was added to BabyScreen+ newborn screening. Sources: Expert list treatable, haematological tags were added to gene: FECH. Mode of inheritance for gene: FECH was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FECH were set to Protoporphyria, erythropoietic, 1, MIM# 177000 Review for gene: FECH was set to GREEN Added comment: Established gene-disease association. Onset of photosensitivity is in infancy/childhood. Treatment: Afamelanotide Non-genetic confirmatory testing: free protoporphyrin Sources: Expert list |
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| BabyScreen+ newborn screening v1.50 | CUL3 |
Zornitza Stark gene: CUL3 was added gene: CUL3 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: CUL3. Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CUL3 were set to Pseudohypoaldosteronism, type IIE 614496 Review for gene: CUL3 was set to GREEN Added comment: Established gene-disease association. Variants in this gene also cause a neurodevelopmental disorder; however, there is some genotype-phenotype correlation literature to help distinguish the two. Results in hyperkalaemia and development of hypertension. However, the onset of hypertension is generally later in life. Treatment: thiazide diuretics normalise biochemical abnormalities Sources: Expert list |
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| BabyScreen+ newborn screening v1.35 | CEBPE |
Zornitza Stark gene: CEBPE was added gene: CEBPE was added to BabyScreen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: CEBPE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CEBPE were set to Specific granule deficiency, MIM# 245480 Review for gene: CEBPE was set to GREEN Added comment: Established gene-disease association. Recurrent infections in infancy and childhood. Treatment: long term antimicrobial prophalaxis Non-genetic confirmatory testing available Sources: Expert Review |
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| BabyScreen+ newborn screening v1.31 | C2 |
Zornitza Stark gene: C2 was added gene: C2 was added to BabyScreen+ newborn screening. Sources: Expert list Mode of inheritance for gene: C2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2 were set to 31421540 Phenotypes for gene: C2 were set to C2 deficiency, MIM# 217000 Review for gene: C2 was set to GREEN Added comment: Established gene-disease association. Can present with severe early infections in infancy/childhood. Later manifestations include autoimmune phenomena. Treatment: pneumococcal, meningococcal, haemophilus influenzae vaccines Non-genetic confirmatory tests: complement levels Sources: Expert list |
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| BabyScreen+ newborn screening v1.30 | APOA5 |
Zornitza Stark gene: APOA5 was added gene: APOA5 was added to BabyScreen+ newborn screening. Sources: Expert list treatable tags were added to gene: APOA5. Mode of inheritance for gene: APOA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: APOA5 were set to 23307945; 31390500 Phenotypes for gene: APOA5 were set to Hyperchylomicronaemia, late-onset, MIM# 144650 Review for gene: APOA5 was set to RED Added comment: Established gene-disease association. Variable age of onset, many of the reported individuals are adults. Treatment: Volanesorsen Sources: Expert list |
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| BabyScreen+ newborn screening v1.28 | AP3D1 |
Zornitza Stark gene: AP3D1 was added gene: AP3D1 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, haematological tags were added to gene: AP3D1. Mode of inheritance for gene: AP3D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP3D1 were set to 26744459; 9697856; 30472485; 36445457 Phenotypes for gene: AP3D1 were set to Hermansky-Pudlak syndrome 10, MIM# 617050 Review for gene: AP3D1 was set to AMBER Added comment: Four individuals from two unrelated families and a mouse model. Borderline gene-disease association. New case report 36445457, proband presenting with SNHL and questionable other subtle features of HPS, homozygous missense variant (VOUS). Onset in infancy. Treatable: BMT for immunodeficiency. Sources: Expert list |
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| BabyScreen+ newborn screening v1.23 | TRAC |
Zornitza Stark gene: TRAC was added gene: TRAC was added to BabyScreen+ newborn screening. Sources: Expert Review founder, technically challenging tags were added to gene: TRAC. Mode of inheritance for gene: TRAC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAC were set to 21206088 Phenotypes for gene: TRAC were set to Immunodeficiency 7, TCR-alpha/beta deficient, MIM#615387 Review for gene: TRAC was set to RED Added comment: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools. Sources: Expert Review |
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| BabyScreen+ newborn screening v1.1 | Zornitza Stark Panel name changed from Baby Screen+ newborn screening to BabyScreen+ newborn screening | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2172 | DLAT |
Zornitza Stark gene: DLAT was added gene: DLAT was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: DLAT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DLAT were set to Pyruvate dehydrogenase E2 deficiency, MIM# 245348 Review for gene: DLAT was set to GREEN Added comment: Well established gene-disease association. Clinical presentation is in infancy. Treatment: ketogenic diet has a significant impact on outcome; some cases responsive to thiamine Non-genetic confirmatory testing: enzymology Included for consistency with PDHA1/PDHX Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2170 | PDHB |
Zornitza Stark gene: PDHB was added gene: PDHB was added to Baby Screen+ newborn screening. Sources: Expert Review treatable, metabolic tags were added to gene: PDHB. Mode of inheritance for gene: PDHB was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PDHB were set to Pyruvate dehydrogenase E1-beta deficiency, MIM# 614111 Review for gene: PDHB was set to GREEN Added comment: Well established gene-disease association. Clinical presentation is in infancy. Treatment: ketogenic diet has a significant impact on outcome; some cases responsive to thiamine Non-genetic confirmatory testing: enzymology Included for consistency with PDHA1/PDHX Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2161 | NLRP3 |
Zornitza Stark gene: NLRP3 was added gene: NLRP3 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: NLRP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NLRP3 were set to 25038238 Phenotypes for gene: NLRP3 were set to Familial cold inflammatory syndrome 1, MIM#120100 Muckle-Wells syndrome, MIM#191900 CINCA syndrome, MIM#607115 Deafness, autosomal dominant 34, with or without inflammation, MIM#617772 Keratoendothelitis fugax hereditaria, MIM#148200 Review for gene: NLRP3 was set to AMBER Added comment: Established gene-disease associations. Variants in this gene cause a spectrum of clinical phenotypes, ranging from onset in infancy to adult-onset, with variable severity. Genotype-phenotype correlation is unclear, hence not suitable for inclusion at this time. Treatment: corticosteroids, anakinra, rilonacept and canakinumab. Non-genetic confirmatory testing: no. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2156 | GLDC |
Zornitza Stark changed review comment from: Severe form likely to present clinically, so milder forms, which are more amenable to treatment are likely to be identified through screening.; to: Severe form likely to present clinically, so milder forms, which are more amenable to treatment are likely to be identified through screening. However, the effectiveness of treatment is not established, PMID 35683414 for a recent review. |
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| BabyScreen+ newborn screening v0.2155 | GLDC | Zornitza Stark commented on gene: GLDC: Severe form likely to present clinically, so milder forms, which are more amenable to treatment are likely to be identified through screening. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2148 | SUFU |
Lilian Downie gene: SUFU was added gene: SUFU was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SUFU were set to PMID: 29186568 Phenotypes for gene: SUFU were set to {Medulloblastoma} MIM#155255 Penetrance for gene: SUFU were set to Incomplete Review for gene: SUFU was set to RED Added comment: Medullobastoma 1st year of life incomplete penetrance worse outcomes no determined screening protocol Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | PAX5 |
Lilian Downie gene: PAX5 was added gene: PAX5 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: PAX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAX5 were set to PMID: 24013638 Phenotypes for gene: PAX5 were set to {Leukemia, acute lymphoblastic, susceptibility to, 3} MIM#615545 Penetrance for gene: PAX5 were set to Incomplete Review for gene: PAX5 was set to RED Added comment: Incomplete penetrance Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | GPR161 |
Lilian Downie gene: GPR161 was added gene: GPR161 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GPR161 were set to PMID: 31609649 Phenotypes for gene: GPR161 were set to Medulloblastoma predisposition syndrome MIM#155255 Penetrance for gene: GPR161 were set to Incomplete Review for gene: GPR161 was set to RED Added comment: Increased risk of medulloblastoma at <3yrs Also identified in population and healthy parents Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | CTR9 |
Lilian Downie gene: CTR9 was added gene: CTR9 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTR9 were set to PMID: 32412586 Phenotypes for gene: CTR9 were set to Wilms tumour predisposition Penetrance for gene: CTR9 were set to Incomplete Review for gene: CTR9 was set to RED Added comment: 9/14 germline variant developed Wilms (in 4 families) Red due to reduced penetrance Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | ALK |
Lilian Downie gene: ALK was added gene: ALK was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ALK were set to PMID: 22071890 Phenotypes for gene: ALK were set to {Neuroblastoma, susceptibility to, 3} MIM#613014 Penetrance for gene: ALK were set to Incomplete Review for gene: ALK was set to RED Added comment: Reduced penetrance Not clear guideline on management if detected Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | TUBB4B |
Lilian Downie gene: TUBB4B was added gene: TUBB4B was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TUBB4B were set to PMID: 29198720, 35240325 Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879 Review for gene: TUBB4B was set to RED Added comment: The TUBB4B gene has been associated with autosomal dominant Leber congenital amaurosis with early-onset deafness Not consistently hearing phenotype <5years therefore excluded Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | SLITRK6 |
Lilian Downie gene: SLITRK6 was added gene: SLITRK6 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SLITRK6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLITRK6 were set to PMID: 23543054, PMID: 25590127 Phenotypes for gene: SLITRK6 were set to Deafness and myopia MIM#221200 Review for gene: SLITRK6 was set to GREEN Added comment: Congenital or prelingual deafness (SNHL or ANSD) high myopia Sources: Expert list |
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| BabyScreen+ newborn screening v0.2148 | MPZL2 |
Lilian Downie gene: MPZL2 was added gene: MPZL2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: MPZL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPZL2 were set to PMID: 29982980, 29961571, 35734045,33234333 Phenotypes for gene: MPZL2 were set to Deafness, autosomal recessive 111 MIM#618145 Review for gene: MPZL2 was set to RED Added comment: Most cases are pre-lingual but 29961571, 35734045 report adult onset so I think should be excluded based on variability of age of onset Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | LMX1A |
Lilian Downie gene: LMX1A was added gene: LMX1A was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: LMX1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMX1A were set to PMID: 29754270 Phenotypes for gene: LMX1A were set to Deafness, autosomal dominant 7 MIM#601412 Review for gene: LMX1A was set to RED Added comment: Age of onset too variable Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | GREB1L |
Lilian Downie gene: GREB1L was added gene: GREB1L was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GREB1L were set to PMID: 29955957, 32585897 Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80 MIM#619274 Review for gene: GREB1L was set to GREEN Added comment: Congenital hearing impairment with cochlear abnormalities This gene also causes Renal hypodysplasia/aplasia 3 MIM#617805 with no clear difference in mutation spectrum Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | CRYM |
Lilian Downie gene: CRYM was added gene: CRYM was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CRYM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRYM were set to PMID: 12471561, 32742378 Phenotypes for gene: CRYM were set to Deafness, autosomal dominant 40 MIM#616357 Review for gene: CRYM was set to RED Added comment: Dominant hearing loss One paper infant onset, the other all adult onset Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | COL4A6 |
Lilian Downie gene: COL4A6 was added gene: COL4A6 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: COL4A6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: COL4A6 were set to PMID: 33840813, PMID: 23714752 Phenotypes for gene: COL4A6 were set to Deafness, X-linked 6 MIM#300914 Review for gene: COL4A6 was set to GREEN Added comment: Pre-lingual or congenital deafness in males consider not reporting in females (may have adult onset hearing impairment) Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | CLDN9 |
Lilian Downie gene: CLDN9 was added gene: CLDN9 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CLDN9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLDN9 were set to PMID: 34265170 Phenotypes for gene: CLDN9 were set to Deafness, autosomal recessive 116 MIM#619093 Review for gene: CLDN9 was set to RED Added comment: Age of onset not consistently <5 Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | CEP250 |
Lilian Downie gene: CEP250 was added gene: CEP250 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CEP250 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP250 were set to PMID: 34223797, PMID: 29718797, PMID: 30459346, PMID: 28005958 Phenotypes for gene: CEP250 were set to Cone-rod dystrophy and hearing loss 2 MIM#618358 Review for gene: CEP250 was set to RED Added comment: Hearing loss and RP Atypical Usher phenotype Age of onset and penetrance of hearing loss component is variable and seeing as this is the treatable component have excluded from list Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | ABHD12 |
Lilian Downie gene: ABHD12 was added gene: ABHD12 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: ABHD12 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ABHD12 were set to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674 Review for gene: ABHD12 was set to RED Added comment: Age of onset not consistently under 5 for treatable elements such as hearing loss. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | CD164 |
Lilian Downie gene: CD164 was added gene: CD164 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66 MIM#616969 Review for gene: CD164 was set to RED Added comment: Green in our mendeliome/deafness but limited evidence by clingen variable age of onset from newborn to 20's reason for exclusion Sources: Expert list |
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| BabyScreen+ newborn screening v0.2141 | AP1B1 |
Lilian Downie gene: AP1B1 was added gene: AP1B1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP1B1 were set to PMID:31630791, 31630788, 33452671 Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive MIM#242150 Review for gene: AP1B1 was set to GREEN Added comment: Icthyosis progressive hearing loss (childhood) often detected newborn screening photophobia corneal scarring/keratitis variable dev delay part of copper metabolism pathway but no proven treatment Sources: Expert list |
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| BabyScreen+ newborn screening v0.2128 | JUP |
Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be earlier onset, more severe.; to: Discussed potentially just screening for bi-allelic disease as can be earlier onset, more severe. Discussed further with a paediatric cardiologist: variable age of onset and penetrance, therefore does not meet criteria. |
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| BabyScreen+ newborn screening v0.2127 | DSP |
Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be more severe, earlier onset.; to: Discussed screening for bi-allelic disease as can be more severe, earlier onset. Also discussed with paediatric cardiologist: variable age of onset and penetrance, exclude. |
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| BabyScreen+ newborn screening v0.2118 | TUBB1 |
Zornitza Stark gene: TUBB1 was added gene: TUBB1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TUBB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TUBB1 were set to 30446499 Phenotypes for gene: TUBB1 were set to Congenital hypothyroidism, MONDO:0018612, TUBB1-related; Macrothrombocytopenia, autosomal dominant, TUBB1-related, OMIM # 613112 Review for gene: TUBB1 was set to GREEN Added comment: At least 3 families reported with congenital hypothyroidism associated with TUBB1 variants. Platelet abnormalities reported. Treatment: thyroxine. Non-genetic confirmatory testing: TFTs, blood film. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2116 | SLC26A7 |
Zornitza Stark gene: SLC26A7 was added gene: SLC26A7 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: SLC26A7. Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321 Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related Review for gene: SLC26A7 was set to GREEN Added comment: More than 10 unrelated families reported. Congenital hypothyroidism. Treatment: thyroxine. Should be detected through standard NBS. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2114 | OTX2 |
Zornitza Stark gene: OTX2 was added gene: OTX2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: OTX2. Mode of inheritance for gene: OTX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OTX2 were set to 18728160; 35320640; 33950863 Phenotypes for gene: OTX2 were set to Pituitary hormone deficiency, combined, 6, MIM# 613986 Review for gene: OTX2 was set to GREEN Added comment: Variants in this gene have been associated with pituitary hormone deficiency with or without microphthalmia, including of TSH. Congenital onset. Microphthalmia would present clinically in the newborn period. Infants with TSH deficiency should be detected by standard NBS. Treatment: thyroxine and other hormone replacements. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2109 | CDCA8 |
Zornitza Stark gene: CDCA8 was added gene: CDCA8 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: CDCA8. Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CDCA8 were set to 28025328; 29546359 Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, MONDO:0018612, CDCA8-related Review for gene: CDCA8 was set to GREEN Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. Treatment: thyroxine Likely to be detected on standard NBS. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2103 | TMEM38B |
Zornitza Stark gene: TMEM38B was added gene: TMEM38B was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TMEM38B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM38B were set to 23054245; 28323974 Phenotypes for gene: TMEM38B were set to Osteogenesis imperfecta, type XIV , MIM#615066 Review for gene: TMEM38B was set to GREEN Added comment: More than 10 families reported. Variable severity, onset of fractures generally in infancy. Treatment: bisphosphanates; improvement in BMD reported. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2102 | SPARC |
Zornitza Stark gene: SPARC was added gene: SPARC was added to Baby Screen+ newborn screening. Sources: Expert list skeletal tags were added to gene: SPARC. Mode of inheritance for gene: SPARC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPARC were set to 26027498; 34462290 Phenotypes for gene: SPARC were set to Osteogenesis imperfecta, type XVII, MIM# 616507 Review for gene: SPARC was set to RED Added comment: Established gene-disease association, 5 families reported. Onset of fractures in infancy. Prominent neuromuscular features, MRI brain changes; some with ID. Treatment: bisphosphanates are generally used in OI but the case reports where these have been used do not seem terribly convincing in terms of response/improvement. Exclude for now. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2096 | SERPINH1 |
Zornitza Stark gene: SERPINH1 was added gene: SERPINH1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, skeletal tags were added to gene: SERPINH1. Mode of inheritance for gene: SERPINH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINH1 were set to 29520608; 25510505; 33524049 Phenotypes for gene: SERPINH1 were set to Osteogenesis imperfecta, type X, MIM# 613848 Review for gene: SERPINH1 was set to GREEN Added comment: Established gene-disease association. Onset of fractures is in infancy. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2094 | SERPINF1 |
Zornitza Stark gene: SERPINF1 was added gene: SERPINF1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, skeletal tags were added to gene: SERPINF1. Mode of inheritance for gene: SERPINF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINF1 were set to 28689307 Phenotypes for gene: SERPINF1 were set to Osteogenesis imperfecta, type VI, MIM# 613982 Review for gene: SERPINF1 was set to GREEN Added comment: Established gene-disease association. Onset of fractures is in infancy. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2093 | PPIB |
Zornitza Stark gene: PPIB was added gene: PPIB was added to Baby Screen+ newborn screening. Sources: Expert list skeletal tags were added to gene: PPIB. Mode of inheritance for gene: PPIB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPIB were set to 19781681; 32392875 Phenotypes for gene: PPIB were set to Osteogenesis imperfecta, type IX, MIM# 259440 Review for gene: PPIB was set to RED Added comment: Established gene-diseases association. Most reported families have had severe OI, presenting perinatally, therefore exclude. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2090 | P3H1 |
Zornitza Stark gene: P3H1 was added gene: P3H1 was added to Baby Screen+ newborn screening. Sources: Expert Review treatable, skeletal tags were added to gene: P3H1. Mode of inheritance for gene: P3H1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: P3H1 were set to 17277775; 18566967 Phenotypes for gene: P3H1 were set to Osteogenesis imperfecta, type VIII, (MIM# 610915) Review for gene: P3H1 was set to GREEN Added comment: More than 15 families reported. Congenital onset. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2088 | MESD |
Zornitza Stark gene: MESD was added gene: MESD was added to Baby Screen+ newborn screening. Sources: Expert Review treatable, skeletal tags were added to gene: MESD. Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MESD were set to 31564437; 35092157; 33596325; 31564437 Phenotypes for gene: MESD were set to Osteogenesis imperfecta, type XX, MIM# 618644 Review for gene: MESD was set to GREEN Added comment: More than 5 families reported. Severe form of OI, some perinatal lethal. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.2086 | KDELR2 |
Zornitza Stark gene: KDELR2 was added gene: KDELR2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, skeletal tags were added to gene: KDELR2. Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: KDELR2 were set to Osteogenesis imperfecta 21, MIM# 619131 Review for gene: KDELR2 was set to GREEN Added comment: 4 families with osteogenesis imperfecta reported with functional studies. Onset in infancy. Improvement reported with bisphosphanates, similar to other OI. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2084 | FKBP10 |
Zornitza Stark gene: FKBP10 was added gene: FKBP10 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: FKBP10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FKBP10 were set to 34173012 Phenotypes for gene: FKBP10 were set to Osteogenesis imperfecta, type XI, OMIM:610968 Review for gene: FKBP10 was set to GREEN Added comment: Well established gene-disease association. Early-onset bone fractures and progressive skeletal deformities. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2082 | BMP1 |
Zornitza Stark gene: BMP1 was added gene: BMP1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: BMP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BMP1 were set to 33818922 Phenotypes for gene: BMP1 were set to Osteogenesis imperfecta, type XIII , MIM#614856 Review for gene: BMP1 was set to GREEN Added comment: Rare cause of OI. 20 families reported. Treatment: bisphosphanates. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SARS |
Lilian Downie gene: SARS was added gene: SARS was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SARS were set to PMID:34570399, PMID: 34194004 Phenotypes for gene: SARS were set to Neurodevelopmental disorder with microcephaly, ataxia, and seizures MIM#617709 Review for gene: SARS was set to RED Added comment: developmental delay, deafness, cardiomyopathy, epilepsy, and severe febrile decompensations Rx serine supplementation - limited evidence and sounds supportive only Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SCARB2 |
Lilian Downie gene: SCARB2 was added gene: SCARB2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCARB2 were set to PMID: 34337151, PMID: 35346091, PMID: 26677510 Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure MIM#254900 Review for gene: SCARB2 was set to RED Added comment: Onset not <5 Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SERPING1 |
Lilian Downie gene: SERPING1 was added gene: SERPING1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SERPING1 were set to PMID: 32898710 Phenotypes for gene: SERPING1 were set to Angioedema, hereditary, 1 and 2 MIM#106100 Review for gene: SERPING1 was set to RED Added comment: episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. Age of onset not typically <5 Treatment Purified C1 inhibitor concentrate (Cinryze, Berinert, HAEGARDA, or Ruconest), Ecallantide (Kalbitor), Icatibant (Firazyr), Lanadelumab, Orladeyo (berotralstat), FFP or solvent-detergent treated plasma, antisense oligonucleotide treatment (donidalorsen) Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SGPL1 |
Lilian Downie gene: SGPL1 was added gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SGPL1 were set to PMID: 28165343 Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575 Review for gene: SGPL1 was set to RED Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?) Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SLC1A3 |
Lilian Downie gene: SLC1A3 was added gene: SLC1A3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC1A3 were set to PMID: 32754645 Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6 MIM#612656 Review for gene: SLC1A3 was set to RED Added comment: ataxia occurs with febrile illnesses Episodic attacks lasted 2 to 3 hours and were often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech Not consistently in children <5 and variable severity Suggested Rx acetazolamide Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SMARCD2 |
Lilian Downie gene: SMARCD2 was added gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377 Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475 Review for gene: SMARCD2 was set to GREEN Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects Rx bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SNX10 |
Lilian Downie gene: SNX10 was added gene: SNX10 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNX10 were set to PMID: 30885997, PMID: 22499339 Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 MIM#615085 Review for gene: SNX10 was set to GREEN Added comment: macrocephaly failure to thrive osteopetrosis Rx bone marrow tranplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SORD |
Lilian Downie gene: SORD was added gene: SORD was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SORD were set to PMID: 32367058 Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy MIM#618912 Review for gene: SORD was set to RED Added comment: Slowly progressive, onset not consistently <5 Rx epalrestat and ranirestat Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SOX3 |
Lilian Downie gene: SOX3 was added gene: SOX3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SOX3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SOX3 were set to PMID: 31678974, PMID: 15800844 Phenotypes for gene: SOX3 were set to Panhypopituitarism, X-linked MIM#312000 Review for gene: SOX3 was set to AMBER Added comment: Amber in our mendeliome - reviewed for ID Green in pituitary disorders Xq27.1 duplication most common mechanism - inclusion might be a question of whether we can detect CNV's in this region neonatal hypoglycemia and growth hormone deficiency in addition to variable deficiencies of other pituitary hormones. Brain hypoplasia of the anterior pituitary with hypoplasia or absence of the lower half of the infundibulum Rx Growth hormone, levothyroxine, hydrocortisone Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STAT1 |
Lilian Downie gene: STAT1 was added gene: STAT1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STAT1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STAT1 were set to PMID: 31512162, PMID: 27117246 Phenotypes for gene: STAT1 were set to Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive MIM#613796 Review for gene: STAT1 was set to GREEN Added comment: combined immunodeficiency autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function. gain of function mutations - treat rituxomab complete - treat BMT Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STIM1 |
Lilian Downie gene: STIM1 was added gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041 Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783 Review for gene: STIM1 was set to GREEN Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta Rx bone marrow transpant Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STK4 |
Lilian Downie gene: STK4 was added gene: STK4 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STK4 were set to PMID: 22294732 Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868 Review for gene: STK4 was set to GREEN Added comment: primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect Rx bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | STX16 |
Lilian Downie gene: STX16 was added gene: STX16 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) Publications for gene: STX16 were set to PMID: 33247854, PMID: 34477200, PMID: 29072892 Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB MIM#603233 Review for gene: STX16 was set to GREEN Added comment: characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH without other features of Albright hereditary osteodystrophy Rx Calcium, calcitriol, levothyroxine, growth hormone Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | SYT2 |
Lilian Downie gene: SYT2 was added gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SYT2 were set to PMID: 32250532, 32776697 Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461 Review for gene: SYT2 was set to GREEN Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. Only report biallelic for newborn screening ? monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | TBL1X |
Lilian Downie gene: TBL1X was added gene: TBL1X was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TBL1X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: TBL1X were set to PMID: 27603907 Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 MIM#301033 Review for gene: TBL1X was set to GREEN Added comment: Small thyroid gland Detected on newborn screening Can affect carrier females but more mildly Association with deafness Rx thyroxine Sources: Expert list |
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| BabyScreen+ newborn screening v0.2063 | TF |
Lilian Downie gene: TF was added gene: TF was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TF were set to PMID: 32028041, PMID: 19579082, PMID: 11110675 Phenotypes for gene: TF were set to Atransferrinemia MIM#209300 Review for gene: TF was set to GREEN Added comment: Hypochromic microcytic anaemia from absent transferrin - presents in infancy Rx Red cell transfusions, deferoxamine Sources: Expert list |
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| BabyScreen+ newborn screening v0.2062 | SAR1B |
Zornitza Stark gene: SAR1B was added gene: SAR1B was added to Baby Screen+ newborn screening. Sources: Expert list treatable, gastrointestinal tags were added to gene: SAR1B. Mode of inheritance for gene: SAR1B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SAR1B were set to Chylomicron retention disease, MIM# 246700 Review for gene: SAR1B was set to GREEN Added comment: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. Well established gene-disease association. Congenital onset. Treatment: low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K) and oral essential fatty acid supplementation Non-genetic confirmatory testing: total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol Sources: Expert list |
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| BabyScreen+ newborn screening v0.2060 | SAMD9L |
Zornitza Stark gene: SAMD9L was added gene: SAMD9L was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological, haematological tags were added to gene: SAMD9L. Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SAMD9L were set to 31306780 Phenotypes for gene: SAMD9L were set to Ataxia-pancytopenia syndrome, MIM# 159550 Review for gene: SAMD9L was set to GREEN Added comment: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism. Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Treatment: BMT. Non-genetic confirmatory testing: no. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2058 | SAMD9 |
Zornitza Stark gene: SAMD9 was added gene: SAMD9 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SAMD9 were set to 31306780 Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053 Review for gene: SAMD9 was set to GREEN Added comment: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection. Treatment: BMT. Non-genetic confirmatory testing: no. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | THAP11 |
Lilian Downie gene: THAP11 was added gene: THAP11 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: THAP11 were set to PMID: 28449119, PMID: 31905202 Phenotypes for gene: THAP11 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 2 Review for gene: THAP11 was set to RED Added comment: Single patient? Not in our mendeliome Not enough gene disease validity Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | TMEM165 |
Lilian Downie gene: TMEM165 was added gene: TMEM165 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TMEM165 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM165 were set to PMID: 28323990, PMID: 35693943, PMID: 22683087 Phenotypes for gene: TMEM165 were set to Congenital disorder of glycosylation, type IIk MIM#614727 Review for gene: TMEM165 was set to AMBER Added comment: Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern Rx D-galactose (single paper, 2 unrelated patients and an in vitro study) ?inadequete evidence for treatment? Might need to check with JC if we would offer it maybe include Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | TNFRSF13B |
Lilian Downie gene: TNFRSF13B was added gene: TNFRSF13B was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TNFRSF13B were set to PMID: 31681716, PMID: 18981294 Phenotypes for gene: TNFRSF13B were set to Immunodeficiency, common variable, 2 MIM#240500 Review for gene: TNFRSF13B was set to RED Added comment: hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal. I think the age of onset is too variable . Rx immunoglobulin Sources: Expert list |
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| BabyScreen+ newborn screening v0.2052 | TNFAIP3 |
Lilian Downie gene: TNFAIP3 was added gene: TNFAIP3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNFAIP3 were set to PMID: 31587140, PMID: 33101300 Phenotypes for gene: TNFAIP3 were set to Autoinflammatory syndrome, familial, Behcet-like 1 MIM#616744 Review for gene: TNFAIP3 was set to RED Added comment: Average age of onset 5yrs - too variable re age of onset. painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells. Treatment: Colchicine, glucocorticoid, mesalazine, cyclosporine, methotrexate, azathioprine, anakinra, rituximab, tocilizumab, infliximab Sources: Expert list |
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| BabyScreen+ newborn screening v0.2051 | RNPC3 |
Zornitza Stark gene: RNPC3 was added gene: RNPC3 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: RNPC3. Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182 Phenotypes for gene: RNPC3 were set to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160 Review for gene: RNPC3 was set to GREEN Added comment: Three unrelated individuals reported with combined and isolated pituitary hormone deficiencies, including GH and TSH. Onset: congenital. Treatment: GH, thyroxine. Non-genetic confirmatory testing: hormone levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2049 | RASGRP1 |
Zornitza Stark gene: RASGRP1 was added gene: RASGRP1 was added to Baby Screen+ newborn screening. Sources: Literature treatable, immunological tags were added to gene: RASGRP1. Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RASGRP1 were set to Immunodeficiency 64 (MIM#618534) Review for gene: RASGRP1 was set to GREEN Added comment: Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity. Severe disorder, fatal outcomes reported in childhood. Treatment: BMT. Non-genetic confirmatory testing: no. Sources: Literature |
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| BabyScreen+ newborn screening v0.2046 | RAC2 |
Zornitza Stark gene: RAC2 was added gene: RAC2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: RAC2. Mode of inheritance for gene: RAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RAC2 were set to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 Review for gene: RAC2 was set to GREEN Added comment: Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia 13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R) These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia. SCID-like phenotype. Treatment: IVIG, BMT Note evidence for the other two immunodeficiency disorders associated with this gene is limited. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2044 | PLS3 |
Zornitza Stark gene: PLS3 was added gene: PLS3 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: PLS3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043 Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis - MIM#300910 Review for gene: PLS3 was set to GREEN Added comment: Females mildly affected: exclude from screening. Presentation in males similar to OI, though also variable in severity. Treatment: safe handling techniques, bisphosphonates, pamidronate, zoledronic acid, teriparatide, denosumab, alendronate Non-genetic confirmatory testing: skeletal survey Sources: Expert list |
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| BabyScreen+ newborn screening v0.2042 | OTULIN |
Zornitza Stark gene: OTULIN was added gene: OTULIN was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: OTULIN. Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 Review for gene: OTULIN was set to GREEN Added comment: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection. Onset is generally in infancy. Treatment: inflixiimab, anakinra, etanercept, corticosteroids. Non-genetic confirmatory testing: no. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2040 | OAS1 |
Zornitza Stark gene: OAS1 was added gene: OAS1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: OAS1. Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OAS1 were set to 34145065; 29455859 Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042 Review for gene: OAS1 was set to GREEN Added comment: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood. Treatment: IVIG; BMT is curative. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2038 | NFKBIA |
Zornitza Stark gene: NFKBIA was added gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: NFKBIA. Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132 Review for gene: NFKBIA was set to GREEN Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual). Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity. The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands). Onset is generally in infancy. Treatment: BMT. Non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v0.2037 | NAXE |
Zornitza Stark gene: NAXE was added gene: NAXE was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: NAXE. Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAXE were set to 27122014; 27616477; 31758406 Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186 Review for gene: NAXE was set to RED Added comment: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported. Treatment: niacin However, single case reported. Treatment not established. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2035 | NAXD |
Zornitza Stark gene: NAXD was added gene: NAXD was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: NAXD. Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAXD were set to 30576410; 31755961; 32462209; 35231119 Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321 Review for gene: NAXD was set to AMBER Added comment: Seven unrelated cases, episodes of fever/infection prior to deterioration reported. Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy; another with progressive encephalopathy with brain oedema. Patient cells and muscle biopsies also showed impaired mitochondrial function, higher sensitivity to metabolic stress, and decreased mitochondrial reactive oxygen species production. In vitro functional assays also conducted. Treatment: niacin However, only two cases reported. Treatment not established. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2033 | MYD88 |
Zornitza Stark gene: MYD88 was added gene: MYD88 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MYD88. Mode of inheritance for gene: MYD88 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYD88 were set to 18669862; 20538326; 31301515 Phenotypes for gene: MYD88 were set to Immunodeficiency 68, MIM# 612260 Review for gene: MYD88 was set to GREEN Added comment: Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed. At least 7 families and a mouse model. Treatment: Prophylactic antibiotic treatment, pneumococcal, meningococcal, haemophilus influenzae vaccines, and immunoglobulin replacement. Non-genetic confirmatory testing: toll-like receptor function Sources: Expert list |
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| BabyScreen+ newborn screening v0.2032 | MTHFS |
Zornitza Stark gene: MTHFS was added gene: MTHFS was added to Baby Screen+ newborn screening. Sources: Expert list metabolic tags were added to gene: MTHFS. Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFS were set to 30031689; 31844630; 22303332 Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367 Review for gene: MTHFS was set to RED Added comment: Established gene-disease association. Onset in infancy. Severe disorder. Treatment: single report of some improvement with combination of oral L-5- methyltetrahydrofolate and intramuscular methylcobalamin Sources: Expert list |
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| BabyScreen+ newborn screening v0.2030 | MTHFD1 |
Zornitza Stark gene: MTHFD1 was added gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological, haematological tags were added to gene: MTHFD1. Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFD1 were set to 32414565; 19033438 Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780 Review for gene: MTHFD1 was set to GREEN Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models 7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites. Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases. Treatment: hydroxocobalamin, folinic acid and betaine Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF Sources: Expert list |
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| BabyScreen+ newborn screening v0.2028 | MNX1 |
Zornitza Stark gene: MNX1 was added gene: MNX1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: MNX1. Mode of inheritance for gene: MNX1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MNX1 were set to 36586106 Phenotypes for gene: MNX1 were set to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related Review for gene: MNX1 was set to GREEN Added comment: Three unrelated families reported. Presentation is in newborn period. Treatment: insulin. Non-genetic confirmatory testing: glucose tolerance test, hemoglobin A1C, insulin level, glucose level Sources: Expert list |
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| BabyScreen+ newborn screening v0.2026 | MALT1 |
Zornitza Stark gene: MALT1 was added gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MALT1. Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468 Review for gene: MALT1 was set to GREEN Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency. Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains. All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation. Treatment: prophylactic antibiotics, IVIG, BMT. Non-genetic confirmatory testing: no Sources: Expert list |
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| BabyScreen+ newborn screening v0.2024 | MAGT1 |
Zornitza Stark gene: MAGT1 was added gene: MAGT1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MAGT1. Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: MAGT1 were set to 31036665; 31714901 Phenotypes for gene: MAGT1 were set to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853) Review for gene: MAGT1 was set to GREEN Added comment: XMEN is an X-linked recessive immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Variable age of onset, including in early childhood. Treatment: Mg supplementation; IVIG, BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, Carbohydrate deficient glycosylation profile Sources: Expert list |
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| BabyScreen+ newborn screening v0.2022 | LRBA |
Zornitza Stark gene: LRBA was added gene: LRBA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: LRBA. Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRBA were set to 22608502; 22721650; 25468195; 26206937; 33155142; 31887391 Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700 Review for gene: LRBA was set to GREEN Added comment: Well established gene-disease association. Generally childhood onset with recurrent infections and autoimmune phenomena. Treatment: abatacept, BMT. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2020 | LIG1 |
Zornitza Stark gene: LIG1 was added gene: LIG1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: LIG1. Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG1 were set to 30395541 Phenotypes for gene: LIG1 were set to Immunodeficiency 96, MIM# 619774 Review for gene: LIG1 was set to GREEN Added comment: Established gene-disease association. Onset is generally in early childhood. Presents with recurrent severe infections. Treatment: IVIG, BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, complete blood count Sources: Expert list |
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| BabyScreen+ newborn screening v0.2018 | LEP |
Zornitza Stark gene: LEP was added gene: LEP was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: LEP. Mode of inheritance for gene: LEP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LEP were set to 26567097 Phenotypes for gene: LEP were set to Obesity, morbid, due to leptin deficiency (MIM#614962) Review for gene: LEP was set to GREEN Added comment: Established gene-disease association. Onset is in infancy/early childhood. Similar disorders included. Treatment: metreleptin. Non-genetic confirmatory testing: leptin level. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2016 | JAGN1 |
Zornitza Stark gene: JAGN1 was added gene: JAGN1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: JAGN1. Mode of inheritance for gene: JAGN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: JAGN1 were set to 25129144 Phenotypes for gene: JAGN1 were set to Neutropenia, severe congenital, 6, autosomal recessive, MIM# 616022 Review for gene: JAGN1 was set to GREEN Added comment: Established gene-disease association. Typically presents in early childhood with severe infections. Treatment: G-CSF, BMT. Non-genetic confirmatory testing: complete blood count, bone marrow aspiration and biopsy Sources: Expert list |
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| BabyScreen+ newborn screening v0.2013 | ITK |
Zornitza Stark gene: ITK was added gene: ITK was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: ITK. Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITK were set to Lymphoproliferative syndrome 1, MIM# 613011 Review for gene: ITK was set to GREEN Added comment: 7 individuals from 5 unrelated families reported homozygous (missense/ nonsense) ITK variants consistent with Lymphoproliferative syndrome phenotype. Triggered by EBV infection. Two ITK-deficient mouse models demonstrated reduced T cells (CD4+), causing decreased CD4 to CD8 ratio. Patients displayed early onset of features typically including fever, lymphadenopathy, autoimmune disorders, low immunoglobulins and high EBV viral load. Fatal without BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2011 | IRS4 |
Zornitza Stark gene: IRS4 was added gene: IRS4 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: IRS4. Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: IRS4 were set to 30061370 Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035 Review for gene: IRS4 was set to GREEN Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported. Most identified through standard NBS. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2010 | TNFRSF13C |
Lilian Downie gene: TNFRSF13C was added gene: TNFRSF13C was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFRSF13C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFRSF13C were set to PMID: 19666484, PMID: 27250108, PMID: 18025937 Phenotypes for gene: TNFRSF13C were set to Immunodeficiency, common variable, 4 MIM#613494 Review for gene: TNFRSF13C was set to RED Added comment: Amber in our mendeliome Later childhood or adult onset. BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2009 | IL36RN |
Zornitza Stark gene: IL36RN was added gene: IL36RN was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL36RN. Mode of inheritance for gene: IL36RN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL36RN were set to 31286990 Phenotypes for gene: IL36RN were set to Psoriasis 14, pustular, MIM# 614204 Review for gene: IL36RN was set to GREEN Added comment: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein. Variable age of onset but predominantly in infancy/early childhood. Treatment: ustekinumab, secukinumab, etanercept. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2007 | IL2RA |
Zornitza Stark gene: IL2RA was added gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL2RA. Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367 Review for gene: IL2RA was set to GREEN Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation. At least 4 unrelated families reported. Treatment: rapamycin, bone marrow transplant. Confirmatory non-genetic testing: flow cytometric analysis. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2005 | IL21R |
Zornitza Stark gene: IL21R was added gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL21R. Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207 Review for gene: IL21R was set to GREEN Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Onset: infancy/early childhood. Treatment: BMT. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.2003 | IL1RN |
Zornitza Stark gene: IL1RN was added gene: IL1RN was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL1RN. Mode of inheritance for gene: IL1RN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL1RN were set to Interleukin 1 receptor antagonist deficiency, MIM# 612852 Review for gene: IL1RN was set to GREEN Added comment: Severe immunodeficiency, onset in infancy. Multi-system involvement, can be fatal if untreated. Treatment: anakinra, etanercept, methotrexate, corticosteroid Sources: Expert list |
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| BabyScreen+ newborn screening v0.2001 | IKZF1 |
Zornitza Stark gene: IKZF1 was added gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873 Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset. PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation. Included primarily for LoF phenotype. Treatment: IVIG and BMT. Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.2000 | IKBKB |
Zornitza Stark changed review comment from: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells. Treatment: bone marrow transplant. Sources: Expert list; to: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells. Treatment: bone marrow transplant. Limited evidence for mono-allelic disease. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1999 | IKBKB |
Zornitza Stark gene: IKBKB was added gene: IKBKB was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IKBKB. Mode of inheritance for gene: IKBKB was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IKBKB were set to Immunodeficiency 15B, MIM# 615592 Review for gene: IKBKB was set to GREEN Added comment: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells. Treatment: bone marrow transplant. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1997 | IFNGR2 |
Zornitza Stark gene: IFNGR2 was added gene: IFNGR2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IFNGR2. Mode of inheritance for gene: IFNGR2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IFNGR2 were set to Immunodeficiency 28, mycobacteriosis, MIM# 614889 Review for gene: IFNGR2 was set to AMBER Added comment: At least 5 unrelated families reported. Commonest trigger is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude. Treatment: BMT; avoidance of BCG. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1995 | IFNGR1 |
Zornitza Stark gene: IFNGR1 was added gene: IFNGR1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IFNGR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: IFNGR1 were set to Immunodeficiency 27A, mycobacteriosis, AR, MIM# 209950; Immunodeficiency 27B, mycobacteriosis, AD, MIM# 615978 Review for gene: IFNGR1 was set to AMBER Added comment: Variable age of onset. Most common precipitant is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude. Treatment: BMT; avoidance of BCG. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1993 | IFITM5 |
Zornitza Stark gene: IFITM5 was added gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list 5'UTR, treatable, skeletal tags were added to gene: IFITM5. Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609 Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967 Review for gene: IFITM5 was set to GREEN Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316). Variable severity, including within families. However, severe perinatal presentations reported. Treatment: bisphosphanates. Non-genetic confirmatory testing: skeletal survey. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1991 | ICOS |
Zornitza Stark gene: ICOS was added gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: ICOS. Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594 Review for gene: ICOS was set to GREEN Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models. Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion. Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA. Congenital onset. Treatment: replacement immunoglobulin treatment, bone marrow transplant. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1989 | IARS |
Zornitza Stark gene: IARS was added gene: IARS was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IARS were set to 27426735; 34194004 Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093 Review for gene: IARS was set to AMBER Added comment: Established gene-disease association. Congenital, multi-system metabolic disorder. N=1 study of Isoleucine supplementation and protein fortification (2.5mg/kg/day, during illness 3.5 g/kg/day) with some clinical improvement. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TNFRSF1A |
Lilian Downie gene: TNFRSF1A was added gene: TNFRSF1A was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TNFRSF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNFRSF1A were set to PMID: 11175303, PMID: 32066461, PMID: 29773275, PMID: 32831641 Phenotypes for gene: TNFRSF1A were set to Periodic fever, familial MIM#142680 Penetrance for gene: TNFRSF1A were set to Incomplete Review for gene: TNFRSF1A was set to RED Added comment: Strong gene disease association Childhood onset but age not consistently under 5 and cases of adult onset reports of variable penetrance Rx NSAIDs, corticosteroids, Etanercept , anakinra, canakinumab, tocilizumab because there is no non-molecular confirmatory test I think should be red for variability of age of onset and severity of symptoms. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TOP2B |
Lilian Downie gene: TOP2B was added gene: TOP2B was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TOP2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TOP2B were set to PMID: 31409799, PMID: 35063500, PMID: 32128574, PMID: 33459963 Phenotypes for gene: TOP2B were set to B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296 Review for gene: TOP2B was set to AMBER Added comment: congenital onset humoral immunodeficiency with undetectable B cells, distal limb anomalies, dysmorphic facial features, and urogenital malformations Treatment immunoglobulin (only partially treats phenotype) no literature for evidence around immunoglobulin treatment. Suggest RED but maybe discuss with immunologist? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TPK1 |
Lilian Downie gene: TPK1 was added gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275 Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458 Review for gene: TPK1 was set to GREEN Added comment: Strong gene disease association Variable age of onset but always under 5years Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TRNT1 |
Lilian Downie gene: TRNT1 was added gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905 Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084 Review for gene: TRNT1 was set to AMBER Added comment: Onset infancy Strong gene disease association Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013). Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR. DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1982 | TRPM6 |
Lilian Downie gene: TRPM6 was added gene: TRPM6 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRPM6 were set to PMID: 35903165, PMID: 18818955 Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal MIM#602014 Review for gene: TRPM6 was set to GREEN Added comment: Hypomagnaesemia and hypocalcaemia Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009). Sources: Expert list |
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| BabyScreen+ newborn screening v0.1977 | HSD11B2 |
Zornitza Stark gene: HSD11B2 was added gene: HSD11B2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: HSD11B2. Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025 Review for gene: HSD11B2 was set to GREEN Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone. More than 10 unrelated families reported. Onset is usually in infancy or early childhood. Non-genetic confirmatory testing: aldosterone, renin, potassium levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.1975 | HOGA1 |
Zornitza Stark gene: HOGA1 was added gene: HOGA1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: HOGA1. Mode of inheritance for gene: HOGA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HOGA1 were set to 20797690; 21896830; 22391140 Phenotypes for gene: HOGA1 were set to Hyperoxaluria, primary, type III MIM#613616 Review for gene: HOGA1 was set to GREEN Added comment: Well-established association with primary hyperoxaluria type III. c.700+5G>T is a recurrent pathogenic variant in European populations (possibly founder) and has high frequency in gnomad (0.2-0.3%). Onset in infancy, progressive multi-system disorder. Treatment: pyridoxine, drinking large volumes, alkalinzation of urine, pyrophosphate-containing solutions, liver-kidney transplant Non-genetic confirmatory testing: urinary oxalate Sources: Expert list |
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| BabyScreen+ newborn screening v0.1974 | UMPS |
Lilian Downie gene: UMPS was added gene: UMPS was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: UMPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UMPS were set to PMID: 9042911, PMID: 28205048, PMID: 25757096, PMID: 33489760 Phenotypes for gene: UMPS were set to Orotic aciduria MIM#258900 Review for gene: UMPS was set to GREEN Added comment: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Treat uridine Very rare only 20 cases but treatable. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1974 | UNG |
Lilian Downie gene: UNG was added gene: UNG was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: UNG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNG were set to PubMed: 12958596, PMID: 15967827, PMID: 19202054, PMID: 16860315 Phenotypes for gene: UNG were set to Immunodeficiency with hyper IgM, type 5 MIM#608106 Review for gene: UNG was set to RED Added comment: normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations. susceptibility to bacterial infections, lymphoid hyperplasia only 3 patients reported in a single paper ? Rx immunoglobulin replacement according to Rx genes but I can't find actual papers - i don't think there is enough evidence regarding age of onset or treatability. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1973 | HELLS |
Zornitza Stark gene: HELLS was added gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911 Review for gene: HELLS was set to GREEN Added comment: Congenital onset. Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported. Treatment: bone marrow transplant. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1967 | GPIHBP1 |
Zornitza Stark gene: GPIHBP1 was added gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPIHBP1 were set to 31390500 Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome Review for gene: GPIHBP1 was set to GREEN Added comment: Well-established gene-disease association. Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. Treatment: volanesorsen, dietary fat restriction Non-genetic confirmatory testing: triglyceride level Sources: Expert list |
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| BabyScreen+ newborn screening v0.1965 | GHRHR |
Zornitza Stark gene: GHRHR was added gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GHRHR were set to 8528260; 10084571; 11232012 Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157 Review for gene: GHRHR was set to GREEN Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported. Non-genetic confirmatory testing: growth hormone stimulation test Sources: Expert list |
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| BabyScreen+ newborn screening v0.1963 | GHR |
Zornitza Stark gene: GHR was added gene: GHR was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: GHR were set to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500 Review for gene: GHR was set to GREEN Added comment: Well established gene-disease association. Congenital onset. Treatment: growth hormone. Non-genetic confirmatory testing: growth hormone stimulation test Sources: Expert list |
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| BabyScreen+ newborn screening v0.1961 | GH1 |
Zornitza Stark gene: GH1 was added gene: GH1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: GH1 were set to Growth hormone deficiency, isolated, type IA, MIM# 262400; Growth hormone deficiency, isolated, type II, MIM# 173100; Kowarski syndrome, MIM# 262650 Review for gene: GH1 was set to GREEN Added comment: Well established gene-disease association. Congenital onset. Treatment: growth hormone. Non-genetic confirmatory test: growth hormone stimulation test Sources: Expert list |
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| BabyScreen+ newborn screening v0.1959 | GFI1 |
Zornitza Stark gene: GFI1 was added gene: GFI1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GFI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GFI1 were set to 12778173; 20560965; 11810106; 22684987 Phenotypes for gene: GFI1 were set to Neutropenia, severe congenital 2, autosomal dominant, MIM# 613107 Review for gene: GFI1 was set to GREEN Added comment: At least three unrelated families reported, and supportive functional data. Severe congenital immunodeficiency. Treatment: granulocyte colony-stimulating factor (G-CSF), Bone marrow transplant Non-genetic confirmatory testing: FBE. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1958 | USP18 |
Lilian Downie gene: USP18 was added gene: USP18 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: USP18 were set to PMID: 31940699, 27325888, 12833411 Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2 MIM#617397 Review for gene: USP18 was set to AMBER Added comment: antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway Treatment Ruxolitinib (single patient only) - is a single patient with successful treatment enough? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1958 | VKORC1 |
Lilian Downie gene: VKORC1 was added gene: VKORC1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: VKORC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: VKORC1 were set to PMID:14765194, PMID: 26287237 Phenotypes for gene: VKORC1 were set to Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473 Review for gene: VKORC1 was set to AMBER Added comment: Risk of intracranial haemmorhage in first weeks of life Treatable with vitamin K See below summary - feels like should be green for that homozygous mutation but not sure how to manage the gene overall? not report other variants? Monoallelic - warfarin resistance There is only one mutation known to result in the VKCFD2 phenotype. VKORC1:p.Arg98Trp causes diminished vitamin K epoxide reductase (VKOR) activity compared to that of the wild-type enzyme [15]. VKCFD2 patients exhibit severely diminished activities for the VKD coagulation factors and suffer spontaneous or surgery/injury induced bleeding episodes [16,17]. In addition to this haemorrhagic phenotype, abnormalities in epiphyseal growth have been reported in one case [18]. This phenotype is very rare. Worldwide, there are only four unrelated families known to be affected with VKCFD2 [16,17,18]. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1958 | WDR1 |
Lilian Downie gene: WDR1 was added gene: WDR1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WDR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR1 were set to PMID: 32960541, 27994071, 27557945 Phenotypes for gene: WDR1 were set to Periodic fever, immunodeficiency, and thrombocytopenia syndrome MIM#150550 Review for gene: WDR1 was set to GREEN Added comment: Strong gene disease association Phenotype is early onset immunodeficiency with infections ++ and severe stomatitis Treatable with bone marrow transplant. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | WDR72 |
Lilian Downie gene: WDR72 was added gene: WDR72 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR72 were set to PMID: 30028003, PMID: 30779877, PMID:36836560, PMID: 33033857 Phenotypes for gene: WDR72 were set to Distal renal tubular acidosis Review for gene: WDR72 was set to GREEN Added comment: Amelogenesis imperecta - thickened and disoloured dental enamal with RTA Reduced penetrance or variable expression? Some patients only have the tooth phenotype... Presents with polyuria and growth restriction Treat with oral alkali replacement therapy, potassium chloride Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | WIPF1 |
Lilian Downie gene: WIPF1 was added gene: WIPF1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WIPF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WIPF1 were set to PMID: 27742395, PMID: 30450104, PMID: 22231303 Phenotypes for gene: WIPF1 were set to Wiskott-Aldrich syndrome 2 MIM#614493 Review for gene: WIPF1 was set to GREEN Added comment: Infant onset recurrent infections, thrombycytopenia and eczema Immunology testing to correlate Treatment/cure with bone marrow transplant Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | WNK4 |
Lilian Downie gene: WNK4 was added gene: WNK4 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WNK4 were set to PMID: 22073419, PMID: 31795491, PMID: 10869238, Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB MIM#614491 Review for gene: WNK4 was set to GREEN Added comment: Hyperkalaemia and hypertension Hypercalciuria Hypocalcaemia Decreased bone mineral density Renal calcium stones Treatable with thiazide diuretics Variable age of onset from infancy to adulthood but highly effective treatment so leaning toward include. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | ZBTB24 |
Lilian Downie gene: ZBTB24 was added gene: ZBTB24 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB24 were set to PMID: 28128455, 21906047, 21596365, 23486536 Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069 Review for gene: ZBTB24 was set to AMBER Added comment: INfant onset Agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds. Treat immunoglobulin and bone marrow transplant however, this only treats the immune deficiency Consider exclusion due to untreatable ID phenotype? Sources: Expert list |
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| BabyScreen+ newborn screening v0.1952 | ZNF143 |
Lilian Downie gene: ZNF143 was added gene: ZNF143 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF143 were set to PMID: 20301503, PMID: 27349184 Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1 Review for gene: ZNF143 was set to RED Added comment: Not in our mendeliome Single case Sources: Expert list |
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| BabyScreen+ newborn screening v0.1951 | FOLR1 |
Zornitza Stark gene: FOLR1 was added gene: FOLR1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: FOLR1. Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOLR1 were set to 19732866; 30420205; 27743887 Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068 Review for gene: FOLR1 was set to GREEN Added comment: Folate is a neurotransmitter precursor. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function. Treatment: folinic acid Non-genetic confirmatory testing: cerebrospinal fluid 5-methyltetrahydrofolate level Sources: Expert list |
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| BabyScreen+ newborn screening v0.1949 | FCHO1 |
Zornitza Stark gene: FCHO1 was added gene: FCHO1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: FCHO1. Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FCHO1 were set to 32098969; 30822429 Phenotypes for gene: FCHO1 were set to Immunodeficiency 76, MIM# 619164 Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data. Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features. Treatment: bone marrow transplant. Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, immunoglobulin levels Sources: Expert list |
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| BabyScreen+ newborn screening v0.1947 | FAM111A |
Zornitza Stark gene: FAM111A was added gene: FAM111A was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: FAM111A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: FAM111A were set to Kenny-Caffey syndrome, type 2, MIM# 127000 Review for gene: FAM111A was set to GREEN Added comment: Condition is characterised by impaired skeletal development with small and dense bones, short stature, ocular abnormalities, and primary hypoparathyroidism with hypocalcemia. At least 10 unrelated cases reported with de novo missense variants. Intellectual disability/developmental delay is a rare feature of the condition. Treatment: magnesium, calcium and calcitriol or alfacalcidol Non-genetic confirmatory testing: serum calcium, parathyroid hormone level, calcitonin level Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1945 | ERCC6L2 |
Zornitza Stark gene: ERCC6L2 was added gene: ERCC6L2 was added to Baby Screen+ newborn screening. Sources: Expert Review treatable, haematological tags were added to gene: ERCC6L2. Mode of inheritance for gene: ERCC6L2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERCC6L2 were set to 24507776; 27185855 Phenotypes for gene: ERCC6L2 were set to Bone marrow failure syndrome 2, MIM# 615715 Review for gene: ERCC6L2 was set to AMBER Added comment: Trilineage bone marrow failure, learning disabilities, and microcephaly. Three consanguineous families reported, but two with the same truncating variant, founder effect likely. Treatment: bone marrow transplant. Amber rating due to limited number of families reported. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1943 | DOCK2 |
Zornitza Stark gene: DOCK2 was added gene: DOCK2 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: DOCK2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DOCK2 were set to 26083206; 29204803; 33928462; 30826364; 30838481; 11518968 Phenotypes for gene: DOCK2 were set to Immunodeficiency 40 MIM# 616433 Review for gene: DOCK2 was set to GREEN Added comment: 13 unrelated individuals; two mouse models; 10 biallelic mutations found (6 led to premature termination of the protein & 4 missense mutations affecting conserved residues) All patients presented with combined immunodeficiency in infancy (defective IFN-mediated immunity), early onset of invasive bacterial and viral infections, functional defects in T/B/NK cells and elevated IgM (normal IgG/IgA). Treatment: bone marrow transplant. Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1941 | DNASE2 |
Zornitza Stark gene: DNASE2 was added gene: DNASE2 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: DNASE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNASE2 were set to 29259162; 31775019 Phenotypes for gene: DNASE2 were set to Autoinflammatory-pancytopenia syndrome, MIM# 619858 Review for gene: DNASE2 was set to GREEN Added comment: Inflammatory disorder characterized by splenomegaly, glomerulonephritis, liver fibrosis, circulating anti-DNA autoantibodies, and progressive arthritis. Three families and functional data. Treatment: baricitinib Non-genetic confirmatory testing: Interferon signature Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1939 | DNAJC21 |
Zornitza Stark gene: DNAJC21 was added gene: DNAJC21 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687 Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3, MIM# 617052 Review for gene: DNAJC21 was set to GREEN Added comment: Onset of pancytopenia in early childhood; variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies. Treatment: oral pancreatic enzymes, fat-soluble vitamins, blood and/or platelet transfusions, granulocyte-colony stimulation factor, bone marrow transplant Confirmatory non-genetic testing: no; FBE as pancytopenia evolves. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1937 | CYP2R1 |
Zornitza Stark gene: CYP2R1 was added gene: CYP2R1 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: CYP2R1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP2R1 were set to 15128933; 28548312 Phenotypes for gene: CYP2R1 were set to Rickets due to defect in vitamin D 25-hydroxylation deficiency MIM#600081 Review for gene: CYP2R1 was set to GREEN Added comment: At least 6 unrelated families reported. Onset is generally in infancy. Good response to vitamin D (calcifediol (25_OH_D3). Confirmatory non-genetic testing: serum calcium, parathyroid hormone, 25-hydroxy vitamin D levels Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1935 | C17orf62 |
Zornitza Stark gene: C17orf62 was added gene: C17orf62 was added to Baby Screen+ newborn screening. Sources: Expert Review new gene name, treatable, immunological tags were added to gene: C17orf62. Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984 Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease 5, autosomal recessive, MIM# 618935 Review for gene: C17orf62 was set to GREEN Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name) Primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Haematopoietic bone marrow transplant is curative. Non-genetic confirmatory assay: dihydrorhodamine assay Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1933 | CYB561 |
Zornitza Stark gene: CYB561 was added gene: CYB561 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYB561 were set to 29343526; 31822578 Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182 Review for gene: CYB561 was set to GREEN Added comment: Three families reported. Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood. Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa) Non-genetic confirmatory testing: plasma norepinephrine, epinephrine, dopamine Sources: Expert list |
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| BabyScreen+ newborn screening v0.1932 |
Zornitza Stark Panel name changed from gNBS to Baby Screen+ newborn screening Panel status changed from internal to public |
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| BabyScreen+ newborn screening v0.1897 | MAT1A | Zornitza Stark Phenotypes for gene: MAT1A were changed from Methionine adenosyltransferase deficiency to Methionine adenosyltransferase deficiency MIM#250850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1883 | PRDX1 |
Lilian Downie gene: PRDX1 was added gene: PRDX1 was added to gNBS. Sources: Expert list Mode of inheritance for gene: PRDX1 was set to Other Publications for gene: PRDX1 were set to PMID: 20301503, PMID: 29396438, PMID: 34215320, PMID: 33982424 Phenotypes for gene: PRDX1 were set to Methylmalonic aciduria and homocystinuria, cblC type, digenic MIM#277400 Review for gene: PRDX1 was set to GREEN Added comment: Digenic inheritance with mutation in other allele of MMACHC On GUARDIAN and Rx genes list Recently, three individuals who are double heterozygous for pathogenic variants in MMACHC and PRDX1 have been identified. PRDX1 is a neighboring gene on chromosome 1 transcribed from the reverse strand. Variants identified in PRDX1 located at the intron 5 splice acceptor site caused skipping of exon 6, transcription of antisense MMACHC, and hypermethylation of the MMACHC promoter/exon 1, resulting in no gene expression from that allele [Guéant et al 2018]. Treatable with cobalamin, carnitine & diet. NB MMACHC is green on our list, on newborn screening. Sources: Expert list |
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| BabyScreen+ newborn screening v0.1872 | MAT1A | Lilian Downie reviewed gene: MAT1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Methionine adenosyltransferase deficiency MIM#250850; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1865 | TANGO2 |
Ari Horton changed review comment from: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review; to: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 PMID: 35568137 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4–9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504–600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1865 | TANGO2 |
Ari Horton gene: TANGO2 was added gene: TANGO2 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TANGO2 were set to Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental Penetrance for gene: TANGO2 were set to Complete Review for gene: TANGO2 was set to GREEN Added comment: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1860 | HBA1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Congenital onset. Treatable: transfusions, bone marrow transplant. However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? For review.; to: Well established gene-disease association. Congenital onset. Treatable: transfusions, bone marrow transplant. However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? Exclude for now due to technical concerns. |
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| BabyScreen+ newborn screening v0.1859 | F8 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable severity. Treatment: recombinant factor VIII. Gene therapy trial. Non-genetic confirmatory testing: factor VIII levels. Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. For review.; to: Well established gene-disease association. Variable severity. Treatment: recombinant factor VIII. Gene therapy trial. Non-genetic confirmatory testing: factor VIII levels. Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. Intron 1 inversion also common. Excluded for now until we can confirm we can detect inversion. |
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| BabyScreen+ newborn screening v0.1849 | TMEM43 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; to: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years. Note founder variant in Newfoundland. |
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| BabyScreen+ newborn screening v0.1834 | GLA |
Zornitza Stark changed review comment from: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started.; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. Note ERT is licensed in Australia from age 7 years. However, carbamazepine relieves neuropathic pain, which has onset in early childhood. Overall, include. |
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| BabyScreen+ newborn screening v0.1821 | RET |
Zornitza Stark changed review comment from: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: actionable in first 5 years of life?; to: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: some actionability in first 5 years, variants can be stratified in terms of risk. |
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| BabyScreen+ newborn screening v0.1815 | DNAJC12 |
Zornitza Stark gene: DNAJC12 was added gene: DNAJC12 was added to gNBS. Sources: Expert Review treatable, metabolic tags were added to gene: DNAJC12. Mode of inheritance for gene: DNAJC12 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DNAJC12 were set to Hyperphenylalaninemia, mild, non-BH4-deficient, MIM#617384 Review for gene: DNAJC12 was set to GREEN Added comment: Established gene-disease association. Manifests as mild hyperphenylalaninaemia that would be detected on NBS – untreated results in axial hypotonia, dystonia, nystagmus, global developmental delay, and intellectual disability. From Treatable-ID, level 4 evidence that BH4, L-dopa + carbidopa +/-, 5- hydroxytryptophan improves psychomotor/cognitive development/IQ; prevents, halts, or slows clinical deterioration and improves neurological manifestations. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1812 | GCH1 | Zornitza Stark Phenotypes for gene: GCH1 were changed from Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Dystonia, dopa-responsive to Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1808 | GCH1 | Zornitza Stark reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910, Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1801 | MLH1 |
Zornitza Stark changed review comment from: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites; to: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites |
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| BabyScreen+ newborn screening v0.1772 | RUNX1 |
Zornitza Stark gene: RUNX1 was added gene: RUNX1 was added to gNBS. Sources: ClinGen for review, treatable, haematological tags were added to gene: RUNX1. Mode of inheritance for gene: RUNX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RUNX1 were set to Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399 Review for gene: RUNX1 was set to AMBER Added comment: Assessed as 'moderate actionability' in paediatric patients by ClinGen. HTHCPS is characterized by mild to moderate thrombocytopenia with normal platelet size, abnormal platelet functioning (defective release of delta granules and/or aggregation defects), and an increased risk of developing a haematologic malignancy. Age of onset of bleeding can be highly variable, with some individuals presenting in early infancy and others not recognizing their symptoms until much later in life. Severe thrombocytopenia or profound platelet dysfunction can result in recognition during the perinatal or infancy period. Hematologic malignancies can occur in childhood or adulthood; the range of age of onset is wide with a median age of 33 years. Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) can be used for surgeries, injuries, or dental treatments. Platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk. Though there is no specific treatment for HTHCPS, there are recommendations regarding the indications and timing of hematopoietic stem cell transplantation (HSCT) that vary. HSCT in pre-malignancy patients, particularly in the absence of any clonal progression, is debatable due to transplantation-associated risks and incomplete penetrance. Some suggested indications for HSCT include severe or symptomatic cytopenias, severe marrow dysplasia (particularly in the context of falling blood counts), complex or high-risk (e.g., monosomy 7) cytogenetic abnormalities (particularly if the clones are large or increasing in size) and increasing blasts >5%. Consider use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1770 | DICER1 |
Zornitza Stark gene: DICER1 was added gene: DICER1 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: DICER1 were set to DICER1 syndrome, MONDO:0017288 Penetrance for gene: DICER1 were set to Incomplete Review for gene: DICER1 was set to AMBER Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen. A multiple registry study examining neoplasm incidence in a cohort containing 102 non-probands with DICER1 pathogenic variants (3,344 person-years of observation in non-probands) found that by age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of non-probands had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of non-probands had developed a neoplasm (females, 26.5%; males, 10.2%). Most individuals with pathogenic variants in DICER1 are healthy or have only minor DICER1-associaited conditions. The most severe manifestations tend to present in early childhood with adulthood characterized by good health. The majority of tumors in individuals with DICER1 pathogenic variants occur in individuals younger than 40. Many of these tumors typically only occur in childhood, including: PPB (before age 7), CN (before age 4), CBME typically occurs in young children, pituitary blastoma (before age 2), and childhood pineoblastoma (only one has been reported associated with a DICER1 mutation). Surveillance recommendations: In order to detect pulmonary cysts or PPB (one of the most important causes of DICER1-associated morbidity and mortality), chest x-rays are recommended every 6 months from birth to through age 7 years and then annually from 8-12 years. A chest computed tomography (CT) (with efforts to minimize radiation) should be obtained by 9 months of age, preferably between 3 and 6 months of age and repeated at approximately 2.5 years of age. Abdominal ultrasound is recommended for the detection in infancy or at the time of the first chest CT then every 6-12 months until at least 8 years of age. Annual ultrasound may be considered until 12 years of age. Beginning at ages 8-10 females should receive pelvic ultrasound performed in conjunction with abdominal ultrasound (every 6-12 months) until at least age 40 or as needed for signs and symptoms. Individuals should undergo thyroid ultrasound with assessment for regional adenopathy every 2 to 3 years starting at age 8 or as needed for signs and symptoms. An annual routine dilated ophthalmologic exam with visual acuity screening is recommended from age 3 to at least age 10 for detection of CBME. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1753 | OAT |
Zornitza Stark gene: OAT was added gene: OAT was added to gNBS. Sources: ClinGen for review, treatable, metabolic tags were added to gene: OAT. Mode of inheritance for gene: OAT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: OAT were set to Gyrate atrophy of choroid and retina with or without ornithinemia MIM#258870 Review for gene: OAT was set to GREEN Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen. GA due to deficiency of the enzyme ornithine aminotransferase (OAT) is characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. GA first presents as night blindness and constriction of the visual field caused by sharply demarcated circular areas of chorioretinal atrophy in the periphery. Atrophic areas progressively increase, coalesce, and spread towards the macula leading to central visual loss and blindness (vision less than 20/200). Age at diagnosis ranges from 1 month to 44 years. The condition is characterized by the development of chorioretinal atrophic patches that start in the mid-peripheral retina in the first decade of life. Myopia, night blindness, changes in the macula (including cystic changes), and visual field affection usually start in the first or second decade. Most patients with GA have posterior subcapsular cataracts by the end of the second decade. Irreversible loss of vision and blindness generally occurs between 40 and 55 years of age but is highly variable. Treatment of GA consists mainly of dietary modifications to help lower elevated systemic ornithine levels. Restriction of dietary arginine, a precursor of ornithine, appears to have therapeutic value. Pediatric patients undergoing arginine restriction should receive enough calories in their diet supplemented by essential amino acids, vitamins, and minerals to avoid malnutrition and excessive break down of endogenous proteins. A long-term observational study of 27 patients with GA, 17 who complied with the arginine-restricted diet and 10 who were noncompliant, found that at 14 years follow-up the rates of vision loss were significantly slower in the compliant group for 3 of the 4 outcome measures, when adjusted for age. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1748 | PRKAR1A |
Zornitza Stark edited their review of gene: PRKAR1A: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen, principally due to benefit from early detection of cardiac myxomas through surveillance. CNC is associated with skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number at puberty, fade after the fourth decade, but may still be evident in the eighth decade. Cutaneous myxomas appear between birth and the fourth decade. Cardiac myxomas may occur at a young age. Breast myxomas occur in females after puberty. Males and females may develop nipple myxomas at any age. In a minority of individuals, PPNAD presents in the first two to three years; in the majority, it presents in the second or third decade. LCCSCT often present in the first decade. Signs and symptoms of CNC may be present at birth, but the median age of diagnosis is 20 years. Most patients with CNC present with a mild increase in GH. However, clinically evident acromegaly is a relatively frequent manifestation of CNC, occurring in approximately 10% of adults at the time of presentation. Most individuals with CNC have a normal life span. However, because some die at an early age, the average life expectancy for individuals with CNC is 50 years. Causes of death include complications of cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, and surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors. The only preventive measure in an asymptomatic individual is surgical removal of a heart tumor (cardiac myxoma) prior to the development of heart dysfunction, stroke, or other embolism. Cardiac myxomas should be diagnosed early through regular screening. Development of metabolic abnormalities from Cushing syndrome or arthropathy and other complications from acromegaly may be prevented by medical or surgical treatment of the respective endocrine manifestations. The overall penetrance of CNC in those with a PRKAR1A pathogenic variant is greater than 95% by age 50 years. 30-60% have cardiac myxomas.; Changed rating: GREEN; Changed phenotypes: Carney complex, type 1, MIM# 160980 |
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| BabyScreen+ newborn screening v0.1740 | TGFB2 |
Zornitza Stark gene: TGFB2 was added gene: TGFB2 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: TGFB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: TGFB2 were set to Loeys-Dietz syndrome 4, MIM# 614816 Review for gene: TGFB2 was set to GREEN Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen. Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms which are the major source of morbidity and mortality. Aortic growth can be faster than 10mm per year. Aortic dissection has been observed in early childhood, and the mean age of death is 26 years. Other life-threatening manifestations include spontaneous rupture of the spleen, bowel, and uterine rupture during pregnancy. Prophylactic surgical repair is typically recommended at an aortic diameter of ≥ 4.2 cm. Beta-blockers or other medications can be used to reduce hemodynamic stress. Consider Medicalert bracelet. Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Because of a high risk of cervical spine instability, a flexion and extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1728 | RPE65 |
Zornitza Stark gene: RPE65 was added gene: RPE65 was added to gNBS. Sources: ClinGen for review, treatable, ophthalmological tags were added to gene: RPE65. Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794 Review for gene: RPE65 was set to GREEN Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision. In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood. In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups. LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes). For review: availability of therapy? Sources: ClinGen |
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| BabyScreen+ newborn screening v0.1701 | GLA |
Zornitza Stark changed review comment from: For review: screen only for males or include both?; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. |
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| BabyScreen+ newborn screening v0.1591 | PQBP1 | Zornitza Stark Phenotypes for gene: PQBP1 were changed from Mental retardation to Renpenning syndrome, MIM#309500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1589 | PQBP1 | Zornitza Stark reviewed gene: PQBP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renpenning syndrome, MIM#309500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1469 | ORAI1 |
Zornitza Stark gene: ORAI1 was added gene: ORAI1 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: ORAI1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ORAI1 were set to Immunodeficiency 9, MIM# 612782 Review for gene: ORAI1 was set to GREEN Added comment: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence): - Dominant ORAI1 missense variants via a GOF mechanism cause a slowly progressive myopathy (tubular aggregate myopathy/TAM) - Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy) Included here for AR disease. Onset is in newborn period. Life-threatening. Treatment: BMT. Non-genetic confirmatory testing: T cell proliferation assay Sources: Expert Review |
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| BabyScreen+ newborn screening v0.1154 | GNPTG | John Christodoulou reviewed gene: GNPTG: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 20301784; Phenotypes: Growth rate deceleration, Joint stiffness of the fingers, shoulders, and hips, Gradual mild coarsening of facial features, Genu valgum, scoliosis, hyperlordosis, mitral valve thickening; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1094 | SLC18A2 |
Seb Lunke changed review comment from: Established gene-disease association. Childhood onset neurological condition. Treatment: L-dopa resulted in severe exacerbation of the symptoms. Dopamine receptor agonist (pramipexole) resulted in improvement in symptoms. Earlier treatment more beneficial. Evidence from single family with benefits shown in 4 affected children. Non-genetic confirmatory test: blood pressure measurement and sodium, potassium, aldosterone, renin levels; to: Established gene-disease association. Childhood onset neurological condition. Treatment: L-dopa resulted in severe exacerbation of the symptoms. Dopamine receptor agonist (pramipexole) resulted in improvement in symptoms. Earlier treatment more beneficial. Evidence from single family with benefits shown in 4 affected children. Non-genetic confirmatory test: whole blood serotonin level |
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| BabyScreen+ newborn screening v0.1052 | BMPR1A |
Zornitza Stark changed review comment from: Well established gene-disease association. Polyposis: onset in childhood although cancer onset tends to be in adulthood. For review.; to: Well established gene-disease association. Polyposis: onset in childhood although cancer onset tends to be in adulthood. Screening typically starts in adolescence. |
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| BabyScreen+ newborn screening v0.914 | ENG |
Zornitza Stark changed review comment from: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). For review.; to: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). Management guidelines also suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.862 | ACVRL1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available. However, management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695.; to: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available but emboli zing AVMs alters their natural history. Management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.862 | PCBD1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. ; to: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. |
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| BabyScreen+ newborn screening v0.787 | CYP27A1 |
John Christodoulou changed review comment from: treatable with chenodeoxycholic acid and pravastatin; GeneReviews - www.ncbi.nlm.nih.gov/books/NBK1409/#ctx.Summary Best effect if started early (PMID: 7964884); to: Onset of disease can be in infancy childhood, with a case made for newborn screening/genetic testing because of effective treatments being available - PMID: 33630770 treatable with chenodeoxycholic acid and pravastatin; GeneReviews - www.ncbi.nlm.nih.gov/books/NBK1409/#ctx.Summary Best effect if started early (PMID: 7964884) |
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| BabyScreen+ newborn screening v0.787 | PCBD1 |
John Christodoulou changed review comment from: is on the current VCGS newborn screening panel; to: is on the current VCGS newborn screening panel by virtue of phenylalanine being the primary first tier metabolite that is analysed. Hyperphenylalaninaemia when present in the newborn is transient. There doesn’t appear to be cognitive impairment if untreated, but some individuals develop diabetes and/or mild hypomagnesaemia later in adolescence. There does not appear to be any evidence that any treatments in infancy would have an effect on these two late effects. See: PMID: 32456656 So, I think we can take this one off the list. |
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| BabyScreen+ newborn screening v0.721 | PCBD1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. For review; to: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. |
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| BabyScreen+ newborn screening v0.662 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. Include bi-allelic disease in gNBS. Continue considering if and when mono-allelic disease should be included. |
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| BabyScreen+ newborn screening v0.648 | CEP78 |
Zornitza Stark changed review comment from: Gene-disease association assessed as 'strong' by ClinGen. Atypical Usher phenotype. However, onset of visual and hearing symptoms is variable, ranging from first to fourth decade, exclude for this reason.; to: Gene-disease association assessed as 'strong' by ClinGen. Atypical Usher phenotype. However, onset of visual and hearing symptoms is variable, ranging from first to fourth decade, exclude for this reason, unlikely to be detected by the newborn hearing screening program. |
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| BabyScreen+ newborn screening v0.591 | GCK | Zornitza Stark reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853), Diabetes mellitus, permanent neonatal 1, AR (MIM#606176), Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485), MODY, type II, AD (MIM#125851); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.585 | CBS |
Zornitza Stark changed review comment from: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability, for review.; to: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability: downgraded to Amber for now. |
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| BabyScreen+ newborn screening v0.585 | ABCC6 |
Zornitza Stark changed review comment from: Well established gene-disease association. Severe disorder with onset in infancy, can be fatal. Treatment available: etidronate. However, note excluded by other screening programs as severity difficult to predict from genotype and gene is also associated with PXE, a milder disorder. There are also technical concerns due to 2x pseudogenes which cause mapping/variant calling issues in exons 1-9.; to: Well established gene-disease association. Severe disorder with onset in infancy, can be fatal. Treatment available: etidronate. However, note excluded by other screening programs as severity difficult to predict from genotype and gene is also associated with PXE, a milder disorder. However, imaging may be able to determine severity. There are also technical concerns due to 2x pseudogenes which cause mapping/variant calling issues in exons 1-9. |
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| BabyScreen+ newborn screening v0.583 | FLAD1 | Zornitza Stark reviewed gene: FLAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31392824; Phenotypes: Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency MIM#255100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.503 | WHRN |
Lilian Downie commented on gene: WHRN: Definitive gene disease association Usher, moderate evidence it can also cause a non syndromic hearing loss phenotype. Congenital hearing impairment, childhood onset visual loss Treatment supportive, clinical trials for retinitis pigmentosa *I think we should keep hearing loss genes on as it's part of traditional newborn screening* |
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| BabyScreen+ newborn screening v0.281 | ASL | Zornitza Stark reviewed gene: ASL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Argininosuccinic aciduria MIM#207900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.279 | ARG1 | Zornitza Stark reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Argininaemia MIM#207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.278 | AHCY | Zornitza Stark reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM#613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.275 | PCBD1 | Zornitza Stark reviewed gene: PCBD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, D , MIM#264070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.275 | QDPR | Zornitza Stark reviewed gene: QDPR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, C, MIM# 261630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.275 | PTS | Zornitza Stark reviewed gene: PTS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, A, MIM# 261640; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.270 | ZNF469 |
Lilian Downie changed review comment from: Well established gene-disease association. Severe, causes blindness in the majority in early childhood but variable. Connective tissue disease spectrum. Can cause ocular rupture. Treatment: lifestyle modification (rupture can occur from minor trauma), protective eyewear and avoidance of contact sports and activities, different surgical techniques have been tried in patients with variable success; to: Well established gene-disease association. Severe, causes blindness in the majority in early childhood but variable. Corneal thinning. Connective tissue disease spectrum, can have systemic features. Ocular rupture causes blindness. Treatment: lifestyle modification (rupture can occur from minor trauma), protective eyewear and avoidance of contact sports and activities, different surgical techniques have been tried in patients with variable success |
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| BabyScreen+ newborn screening v0.270 | CBS |
Zornitza Stark changed review comment from: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen.; to: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability, for review. |
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| BabyScreen+ newborn screening v0.222 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. |
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| BabyScreen+ newborn screening v0.199 | GALT | John Christodoulou commented on gene: GALT: part of newborn screening programs nationally (but not in Victoria) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.188 | ACVRL1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available.; to: Well established gene-disease association. Variable age of symptom onset and severity. No specific treatment available. However, management guidelines suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
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| BabyScreen+ newborn screening v0.119 | AVPR2 |
Zornitza Stark changed review comment from: Well established gene-disease association. Onset in infancy. Causes severe dehydration, can be life-threatening. Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin. Clinical trials.; to: Well established gene-disease association. Onset in infancy. Causes severe dehydration, can be life-threatening. Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin. Clinical trials. Around 10% of variants are large deletions. |
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| BabyScreen+ newborn screening v0.118 | AVP |
Zornitza Stark gene: AVP was added gene: AVP was added to gNBS. Sources: Expert Review treatable, clinical trial tags were added to gene: AVP. Mode of inheritance for gene: AVP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AVP were set to 32052034; 31238300 Phenotypes for gene: AVP were set to Diabetes insipidus, neurohypophyseal MIM#125700 Review for gene: AVP was set to GREEN Added comment: Well established gene-disease association. Onset in childhood with polydipsia and polyuria. Can be life-threatening. Treatment: DDAVP. Clinical trials. Sources: Expert Review |
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| BabyScreen+ newborn screening v0.112 | APRT | Zornitza Stark reviewed gene: APRT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.56 | ABCC6 |
Zornitza Stark changed review comment from: Well established gene-disease association. Severe disorder with onset in infancy, can be fatal. Treatment available: etidronate.; to: Well established gene-disease association. Severe disorder with onset in infancy, can be fatal. Treatment available: etidronate. However, note excluded by other screening programs as severity difficult to predict from genotype and gene is also associated with PXE, a milder disorder. There are also technical concerns due to 2x pseudogenes which cause mapping/variant calling issues in exons 1-9. |
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| BabyScreen+ newborn screening v0.16 | ADK | Zornitza Stark Phenotypes for gene: ADK were changed from Hypermethioninemia due to adenosine kinase deficiency to Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.13 | ADK | Zornitza Stark reviewed gene: ADK: Rating: RED; Mode of pathogenicity: None; Publications: 21963049, 17120046, 33309011; Phenotypes: Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.0 | NIN |
Zornitza Stark gene: NIN was added gene: NIN was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: NIN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NIN were set to Seckel syndrome |
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| BabyScreen+ newborn screening v0.0 | MAT1A |
Zornitza Stark gene: MAT1A was added gene: MAT1A was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: MAT1A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MAT1A were set to Methionine adenosyltransferase deficiency |
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| BabyScreen+ newborn screening v0.0 | IRS1 |
Zornitza Stark gene: IRS1 was added gene: IRS1 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: IRS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: IRS1 were set to Diabetes mellitus, noninsulin dependent |
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| BabyScreen+ newborn screening v0.0 | PTS |
Zornitza Stark gene: PTS was added gene: PTS was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: PTS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PTS were set to Hyperphenylalaninemia, BH4-deficient, A, MIM#261640 |
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| BabyScreen+ newborn screening v0.0 | PCBD1 |
Zornitza Stark gene: PCBD1 was added gene: PCBD1 was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: PCBD1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PCBD1 were set to Hyperphenylalaninemia, BH4-deficient, D, MIM# 264070 |
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| BabyScreen+ newborn screening v0.0 | GCH1 |
Zornitza Stark gene: GCH1 was added gene: GCH1 was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: GCH1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GCH1 were set to Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230 |
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| BabyScreen+ newborn screening v0.0 | FLAD1 |
Zornitza Stark gene: FLAD1 was added gene: FLAD1 was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: FLAD1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FLAD1 were set to Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency, MIM# 255100 |
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| BabyScreen+ newborn screening v0.0 | DOCK8 |
Zornitza Stark gene: DOCK8 was added gene: DOCK8 was added to gNBS. Sources: Expert Review Green,BabySeq Category A gene,BegniNGS Mode of inheritance for gene: DOCK8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DOCK8 were set to Hyper-IgE syndrome, MIM#243700 |
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| BabyScreen+ newborn screening v0.0 | ASL |
Zornitza Stark gene: ASL was added gene: ASL was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ASL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ASL were set to Argininosuccinic aciduria, MIM#207900 |
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| BabyScreen+ newborn screening v0.0 | APRT |
Zornitza Stark gene: APRT was added gene: APRT was added to gNBS. Sources: Expert Review Green,BabySeq Category C gene Mode of inheritance for gene: APRT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: APRT were set to Adenine phosphoribosyltransferase deficiency, MIM# 614723 |
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| BabyScreen+ newborn screening v0.0 | AHCY |
Zornitza Stark gene: AHCY was added gene: AHCY was added to gNBS. Sources: BeginNGS,Expert Review Green Mode of inheritance for gene: AHCY was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: AHCY were set to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM# 613752 |
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| BabyScreen+ newborn screening v0.0 | ADK |
Zornitza Stark gene: ADK was added gene: ADK was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: ADK was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ADK were set to Hypermethioninemia due to adenosine kinase deficiency |
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