| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mendeliome v1.1732 | PRMT9 |
Chirag Patel gene: PRMT9 was added gene: PRMT9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRMT9 were set to PMID: 38561334 Phenotypes for gene: PRMT9 were set to Neurodevelopmental disorder, MONDO:0100500 Review for gene: PRMT9 was set to RED Added comment: A homozygous variant (G189R) in PRMT9 is reported based on large WGS study in 136 consanguineous families - unclear if only found in 1 family and no clinical information on case(s). PMRTs (protein arginine methyltransferases) catalyse post translational modification via arginine methylation. Functional studies showed that the G189R variant abolishes PRMT9's methyltransferase activity - specifically at the R508 residue of SF3B2 RNA (exclusively methylated by PRMT9) - and leads to heavy PRMT9 ubiquitination, and abnormal splicing activity of SF3B2. Knock out mouse model showed PRMT9 loss in excitatory neurons leads to aberrant synapse development and impaired learning and memory. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1660 | TRPV5 |
Sangavi Sivagnanasundram changed review comment from: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. Sources: Other; to: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. PMID: 14679186 TRPV5 knockout mice model was used to assess whether the abolishment of TRPV5 led to a disruption in Ca2+ handling. The effects of the disruption in Ca2+ handling resulted in bone abnormalities in the mice and is likely the cause of idiopathic hypercalciuria. Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1634 | TRPV5 |
Sangavi Sivagnanasundram gene: TRPV5 was added gene: TRPV5 was added to Mendeliome. Sources: Other Mode of inheritance for gene: TRPV5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRPV5 were set to PMID: 38528055 Phenotypes for gene: TRPV5 were set to TRPV5-related hypercalciuria (MONDO:0009550) Review for gene: TRPV5 was set to RED Added comment: Not a well-established gene-disease association. Has only been reported in one consanguineous family. PMID: 38528055 3 individuals from the same family affected with hypercalciuria. Biallelic Met598Val variant was identified in the proband and his two affect sibs Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used. Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1583 | TOGARAM2 |
Naomi Baker gene: TOGARAM2 was added gene: TOGARAM2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TOGARAM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOGARAM2 were set to PMID:38374469 Phenotypes for gene: TOGARAM2 were set to Nonsyndromic genetic hearing loss (MONDO:0019497), TOGARAM2-related Review for gene: TOGARAM2 was set to RED Added comment: Paper reports one individual with bilateral profound hearing loss with a homozygous TOGARAM2 nonsense variant and demonstrated reduced mRNA expression in transfected cells. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1442 | LCK |
Zornitza Stark edited their review of gene: LCK: Added comment: Additional cases: PMID 38100037: Description of a second unrelated patient with novel biallelic missense LCK c.1393T>C, p.C465R variant in a patient from a consanguineous Syrian family with profound T-cell immune deficiency characterized by complete LCK protein expression deficiency and ensuing proximal TCR signaling-and CD4 and CD8-co-receptor-mediated functional and phenotypical defects. PMID: 27087313 reported 3 siblings of a consanguineous family presenting with recurrent pneumonia and severe viral skin disease leading to malignant transformation. The patients had an intronic LCK c.188-2A>G splice site variant resulting in skipping of exon 3 and mRNA decay. Clinical data alongside with CD4+ T-cell lymphocytopenia suggested a hypomorphic LCK deficiency.; Changed rating: GREEN; Changed publications: 22985903, 1579166, 11021796, 27087313, 38100037 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1165 | FTCD |
Bryony Thompson changed review comment from: Well-established gene-disease association (see OMIM entry). Glutamate formiminotransferase deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism. Sources: NHS GMS; to: Glutamate formiminotransferase deficiency is classified as a benign form of folate metabolism disorder and an inborn error of amino acid metabolism without clinically significant phenotype (http://iembase.com/disorder/47). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1155 | COL4A3BP |
Ee Ming Wong changed review comment from: - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo. - Several variants transfected into HeLa cells demonstrated gain of CERT activity - CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT; to: - current HGNC symbol: CERT1 - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo. - Several variants transfected into HeLa cells demonstrated gain of CERT activity - CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1074 | EZH1 |
Zornitza Stark gene: EZH1 was added gene: EZH1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EZH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: EZH1 were set to 37433783 Phenotypes for gene: EZH1 were set to Neurodevelopmental disorder (MONDO:0700092), EZH1-related Review for gene: EZH1 was set to GREEN Added comment: PMID: 37433783 Variants were identified 19 individuals from 14 unrelated families, all sharing a clinical phenotype of a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features. Functional studies have shown that some missense EZH1 variants lead to GOF with increased methyltransferase activity and recessive variants impair EZH1 expression causing loss of function effects. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1071 | GPRC5B |
Lucy Spencer gene: GPRC5B was added gene: GPRC5B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPRC5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GPRC5B were set to 37143309 Phenotypes for gene: GPRC5B were set to Megalencephalic leukoencephalopathy with subcortical cysts 3 620447 Review for gene: GPRC5B was set to GREEN Added comment: PMID: 37143309 Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). 3 unrelated patients had variants in GPRC5B, 2 have the same inframe dup Ile175dup and the third has an in frame dup of Ala177. All 3 were de novo and unaffected siblings did not have the variants. All patients have macrocephaly, delayed motor development, seizures, all had varying degrees of cognitive deficits. 2 also had spasticity, ataxia and dystonia. MRI showed MLC, abnormal and swollen cerebral white matter. Patient cell lines showed reduced regulatory volume decrease, and western blot showed a strong increase in GRPC5B levels in patient lymphoblasts. Together, these findings indicate disturbed volume regulation in lymphoblasts from patients with GPRC5B variants, potentially due to increased GPRC5B levels. Transfected cells caused increased volume-regulated anion channel activity. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1062 | NAA30 |
Sarah Pantaleo gene: NAA30 was added gene: NAA30 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA30 was set to Unknown Publications for gene: NAA30 were set to PMID: 37387332 Penetrance for gene: NAA30 were set to unknown Added comment: Report a de novo heterozygous NAA30 nonsense variant c.244C>T, p.(Gln82*) in a 5yo boy with GDD, ASD, hypotonia, seizures, tracheal cleft and recurrent respiratory infections. Seizures resolved after two weeks of life. Family history of ASD in older sister. Epilepsy in mother, childhood onset. Biochemical studies performed to assess the functional impact of the premature stop codon on catalytic activity. The variant was found to completely disrupt N-terminal acetyltransferase activity using an in vitro acetylation assay. Variant de novo, “in a gene sensitive to loss of heterozygosity”. Limitation of study - have not established whether this gene variant acts in a dominant or recessive manner. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1054 | STX5 |
Ain Roesley gene: STX5 was added gene: STX5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related Review for gene: STX5 was set to AMBER gene: STX5 was marked as current diagnostic Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US). Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start) phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol. Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.896 | CHRM5 |
Elena Savva gene: CHRM5 was added gene: CHRM5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHRM5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHRM5 were set to 37213061 Phenotypes for gene: CHRM5 were set to Congenital anomaly of kidney and urinary tract, (MONDO:0019719), CHRM5-related Review for gene: CHRM5 was set to RED Added comment: PMID: 37213061 - homozygous missense p.(Q184R) in a proband with neurogenic bladder and CAKUT. Additional features were small trabeculated urinary bladder, bilateral severe hydronephrosis, grade V VUR right, chronic kidney disease (stage 4). - Radioligand binding experiments were inconclusive - the missense variant had no effect on receptor expression or binding affinity. - ACh binding assay did show a 2-fold increase (borderline significant), but no effect in secondary messenger accumulation. - Transfected CHO line showed no effect on receptor expression - Described a mouse K/O as having a bladder overactivity No hom PTCs in gnomAD Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.732 | SPTLC1 | Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.731 | SPTLC1 | Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.649 | RRAGD |
Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.649 | RRAGD |
Hazel Phillimore gene: RRAGD was added gene: RRAGD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RRAGD were set to PMID: 34607910 Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis Review for gene: RRAGD was set to GREEN Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.635 | MIR145 |
Lucy Spencer gene: MIR145 was added gene: MIR145 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MIR145 were set to 36649075 Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related Review for gene: MIR145 was set to RED Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p. Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.580 | CCIN |
Chern Lim gene: CCIN was added gene: CCIN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCIN were set to 36546111; 36527329 Phenotypes for gene: CCIN were set to Teratozoospermia Review for gene: CCIN was set to GREEN gene: CCIN was marked as current diagnostic Added comment: Two papers with three unrelated patients with teratozoospermia: PMID: 36546111 - Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia. - Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility. PMID: 36527329 - One consanguineous family reported: homozygous missense, with asthenoteratozoospermia. - Transfected HEK cells showed reduced CCIN protein level. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.563 | SLC26A6 |
Arina Puzriakova gene: SLC26A6 was added gene: SLC26A6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969 Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969) SLC26A6 is currently not associated with any human phenotype in OMIM or G2P. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.338 | APRT | Zornitza Stark reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.173 | PMM2 |
Zornitza Stark edited their review of gene: PMM2: Added comment: Association with HIPKD: Cabezas et al (2017) reported co-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD in 17 children from 11 unrelated families. Patients presented with hyperinsulinaemic hypoglycaemia in infancy and enlarged kidneys with multiple kidney cysts. Some progressed to ESKD and some had liver cysts. Whole-genome linkage analysis in 5 informative families identified a single significant locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, they found in all patients a promoter mutation (c.-167G>T) in PMM2, either homozygous or in trans with PMM2 coding mutations. They found deglycosylation in cultured pancreatic β cells altered insulin secretion. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. They proposed that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. None of the patients exhibited the typical clinical or diagnostic features of CDG1A. Serum transferrin glycosylation was normal in 11 patients who had assessment.; Changed publications: 28108845, 28373276, 32595772; Changed phenotypes: Congenital disorder of glycosylation, type Ia (MIM#212065), Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.147 | CLDN5 |
Zornitza Stark gene: CLDN5 was added gene: CLDN5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLDN5 were set to 35714222 Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related Mode of pathogenicity for gene: CLDN5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: CLDN5 was set to AMBER Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg). One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis. CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.111 | TNFSF13 |
Zornitza Stark gene: TNFSF13 was added gene: TNFSF13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFSF13 were set to 32298700 Phenotypes for gene: TNFSF13 were set to Hypogammaglobulinaemia, MONDO:0015977, TNSF13-related Review for gene: TNFSF13 was set to RED Added comment: Single individual, consanguineous parents. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.7 | PROSER1 |
Zornitza Stark gene: PROSER1 was added gene: PROSER1 was added to Mendeliome. Sources: Expert Review founder tags were added to gene: PROSER1. Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PROSER1 were set to 35229282 Phenotypes for gene: PROSER1 were set to Syndromic disease MONDO:0002254, PROSER1-related Review for gene: PROSER1 was set to RED Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families, likely founder effect. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14603 | GNMT | Zornitza Stark Phenotypes for gene: GNMT were changed from to Glycine N-methyltransferase deficiency MIM#606664; Disorders of the metabolism of sulphur amino acids | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14597 | GOT1 | Zornitza Stark Phenotypes for gene: GOT1 were changed from to Aspartate aminotransferase, serum level of, QTL1, MIM# 614419 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14595 | GOT1 | Zornitza Stark reviewed gene: GOT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aspartate aminotransferase, serum level of, QTL1, MIM# 614419; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14341 | UGT1A1 | Zornitza Stark Phenotypes for gene: UGT1A1 were changed from to Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport); Crigler-Najjar syndrome, type I 218800; Crigler-Najjar syndrome, type II 606785 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14219 | FUT1 | Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants produce the Bombay blood group, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14217 | FUT1 | Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants cause Bombay phenotype, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13876 | APRT | Elena Savva Phenotypes for gene: APRT were changed from to Adenine phosphoribosyltransferase deficiency MIM#614723 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13872 | APRT | Elena Savva reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 3680503, 2227934, 7915931, 1353080; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13798 | KLF4 |
Elena Savva gene: KLF4 was added gene: KLF4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KLF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KLF4 were set to PMID: 35168889; 10431239 Phenotypes for gene: KLF4 were set to Hereditary palmoplantar keratoderma MONDO:0019272, KFL4-related Review for gene: KLF4 was set to GREEN Added comment: PMID: 35168889 - 3 patients from 2 unrelated families with palmoplantar keratoderma. Two variants found, fs and a missense. Functional studies on patient skin biopsy shows "slightly but significantly decreased" protein expression in both children. Gene was shown to bind the DSG1 promoter and regulate expression. Transfected cells showed reduced DSG1 expression. PMID: 10431239 - mouse K/O died shortly after birth due to loss of skin barrier function gnomAD: single het fs in the population Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12738 | PIGA | Zornitza Stark changed review comment from: PIGA 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; to: PMID 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12737 | PIGA | Zornitza Stark edited their review of gene: PIGA: Added comment: PIGA 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; Changed publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024, 34875027; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466, Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12728 | TRAPPC10 |
Naomi Baker gene: TRAPPC10 was added gene: TRAPPC10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC10 were set to PMID: 35298461; 30167849 Phenotypes for gene: TRAPPC10 were set to neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related Review for gene: TRAPPC10 was set to GREEN Added comment: PMID: 35298461 – two Pakistani families reported with homozygous variants. Family 1 has frameshift variant in 8 affected individual and family 2 has missense variant in 2 affected individuals. Patients present with microcephaly, short stature, hypotonia, severe ID and behavioural abnormalities. Seizures also reported in 4/10 individuals. Paper also reported brain abnormalities in null mouse model and other functional in transfected cell lines. PMID: 30167849 – initial report of family 2 above. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12475 | FTCD | Zornitza Stark Phenotypes for gene: FTCD were changed from Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism to Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12472 | FTCD | Zornitza Stark Phenotypes for gene: FTCD were changed from to Glutamate formiminotransferase deficiency MIM#229100; Disorders of histidine, tryptophan or lysine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12183 | OAT | Krithika Murali edited their review of gene: OAT: Added comment: Biallelic variants associated with deficiency of mitochondrial enzyme ornithine aminotransferase and elevation of plasma ornithine levels without elevation of ammonia. Characterized by ocular anomalies; however, neurological and muscular features may also be present.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12049 | LCAT | Alison Yeung Phenotypes for gene: LCAT were changed from to Lecithin:Cholesterol Acyltransferase Deficiency, MIM# 245900; Fish-Eye disease, MIM# 136120 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12046 | LCAT | Alison Yeung reviewed gene: LCAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30720493, 6624548; Phenotypes: Lecithin:Cholesterol Acyltransferase Deficiency, MIM# 245900, Fish-Eye disease, MIM# 136120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12028 | MAT1A | Zornitza Stark Phenotypes for gene: MAT1A were changed from to Hypermethioninemia, persistent, autosomal dominant, due to methionine adenosyltransferase I/III deficiency MIM#250850; Methionine adenosyltransferase deficiency, autosomal recessive MIM#250850; Disorders of the metabolism of sulphur amino acids | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10793 | CHP1 |
Zornitza Stark gene: CHP1 was added gene: CHP1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CHP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHP1 were set to 29379881; 32787936 Phenotypes for gene: CHP1 were set to Spastic ataxia 9, autosomal recessive, MIM #618438 Review for gene: CHP1 was set to GREEN Added comment: 2 different consanguineous families with 2 affected siblings with ataxia (1 paediatric onset, 1 adult onset). 3 of the patients had cerebellar atrophy. WES identified homozygous variants in CHP1 gene in both families (K19del and Arg91Cys), which segregated with the disorder in the family. Decreased CHP1 protein on IHC of cerebellar tissue in family with Arg91Cys variant. In vitro functional expression studies in HEK293 cells showed that the K19del mutation resulted in decreased protein expression, with normal levels of transcript, suggesting defects in protein stability. The mutant protein formed massive protein aggregates in transfected neuronal cell bodies and neurite-like projections, whereas the wildtype protein showed a more uniform distribution. The mutant protein altered CHP1 association into functional complexes and impaired membrane localization of the Na+/H+ transporter NHE1. The findings indicated that the CHP1 mutation likely causes ataxia in an NHE1-dependent manner, resembling the mechanism observed in the Chp1 vacillator mutant mouse. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10518 | PRDM9 |
Zornitza Stark gene: PRDM9 was added gene: PRDM9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRDM9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRDM9 were set to 34257419 Phenotypes for gene: PRDM9 were set to Inherited primary ovarian failure MONDO:0019852 Review for gene: PRDM9 was set to GREEN Added comment: The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. PRDM9 is a meiosis-specific histone H3 methyltransferase and a major determinant of meiotic recombination hotspots in mammals. 3 pathogenic heterozygous variants in PRDM9 identified in 4 patients with POI. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity. Prdm9+/- mice were subfertile, and showed increased percentage of germ cells at abnormal pachytene stage with decreased number of PRDM9-dependent DSBs and insufficient recombination. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10510 | NAA20 |
Zornitza Stark gene: NAA20 was added gene: NAA20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAA20 were set to 34230638 Phenotypes for gene: NAA20 were set to Intellectual disability; Microcephaly; Neurodevelopmental disorder MONDO:0700092 Review for gene: NAA20 was set to GREEN Added comment: 2 consanguineous families with 5 affected individuals with developmental delay, intellectual disability, and microcephaly (-2-4SD). Exome and genome sequencing identified 2 different homozygous variants in NAA20 gene (p.Met54Val and p.Ala80Val), and segregated with affected individuals. N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10289 | KIF12 | Zornitza Stark Phenotypes for gene: KIF12 were changed from Cholestasis; High Gamma-Glutamyltransferase (GGT) to Cholestasis, progressive familial intrahepatic, 8, MIM# 619662 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10257 | MIB1 |
Chern Lim changed review comment from: Luxan 2013 (PMID: 23314057): - V943F, seg with LVNC in 1 fam, (gnomADv2: 43 hets). - R530X, seg with LVNC in 1 fam, (gv2: 13 hets). Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. DCM-association = none by Clingen (9/4/2020), ref Luxan 2013 and other pprs, and mentioned gnomAD had too many LoF variants. De Ligt 2012 (PMID: 23033978): de novo R174H (gnomADv2: 7 hets), indvl with severe ID who also has a de novo R47* in WAC (an AD ID gene with LoF established, variant is P in ClinVar), no other pt-specific pheno provided. Kaplanis 2021 (PMID: 33057194): Developmental disorders paper. - 2 missense variants, de novo: 18-19383967-G-A (p.Glu491Lys, gv2 1 het, gv3 absent, GeneDx), 18-19378124-C-T (Thr391Ile, gv2v3 absent, DDD, de novo, no mention of heart pheno). - Of 6 PTVs, 4 had at least 10 hets each in gnomADv2.; to: Luxan 2013 (PMID: 23314057): - V943F, seg with LVNC in 1 fam, (gnomADv2: 43 hets). - R530X, seg with LVNC in 1 fam, (gv2: 13 hets). Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. DCM-association = none by Clingen (9/4/2020), ref Luxan 2013 and other pprs, and mentioned gnomAD had too many LoF variants. De Ligt 2012 (PMID: 23033978): de novo R174H (gnomADv2: 7 hets), indvl with severe ID who also has a de novo R47* in WAC (an AD ID gene with LoF established, variant is P in ClinVar), no other pt-specific pheno provided. Kaplanis 2021 (PMID: 33057194): Developmental disorders paper. - 2 missense variants, de novo: 18-19383967-G-A (p.Glu491Lys, gv2 1 het, gv3 absent), 18-19378124-C-T (Thr391Ile, gv2v3 absent, DDD, de novo, no mention of heart pheno). - Of 6 PTVs, 4 had at least 10 hets each in gnomADv2. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9607 | COG6 | Zornitza Stark changed review comment from: More than 5 unrelated families reported. Key features include growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. Ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies are prominent. Note Shaheen syndrome, MIM#615328 is an allelic disorder, with overlapping clinical features, but normal transferring isoforms recorded creating confusion about whether it represents a distinct entity.; to: More than 5 unrelated families reported. Key features include growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. Ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies are prominent. Note Shaheen syndrome, MIM#615328 is an allelic disorder, with overlapping clinical features, but normal transferrin isoforms recorded creating confusion about whether it represents a distinct entity. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9392 | OSTC |
Belinda Chong gene: OSTC was added gene: OSTC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OSTC were set to PMID: 32267060 Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation Review for gene: OSTC was set to RED Added comment: A patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis. Patient was homozygous for a canonical splice variant (c.431 + 1G > A), mRNA from patient's fibroblast showed mRNA transcript reduced 80-90%/aberrant splicing - predicting NMD. GnomAD - 10 hets, 0 hom Sources: Literature Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9112 | TF | Zornitza Stark Phenotypes for gene: TF were changed from to Atransferrinaemia MIM# 209300; iron overload; hypochromic anaemia; low serum transferrin; Hemosiderosis of the heart and/or liver; Congestive heart failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9109 | TF | Danielle Ariti reviewed gene: TF: Rating: GREEN; Mode of pathogenicity: None; Publications: 11110675, 3472216; Phenotypes: Atransferrinaemia MIM# 209300, iron overload, hypochromic anaemia, low serum transferrin, Hemosiderosis of the heart and/or liver, Congestive heart failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8834 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8823 | SLC51A |
Zornitza Stark gene: SLC51A was added gene: SLC51A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC51A were set to 31863603 Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484 Review for gene: SLC51A was set to RED Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8807 | VPS50 |
Zornitza Stark gene: VPS50 was added gene: VPS50 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7993 | FARSA | Zornitza Stark edited their review of gene: FARSA: Added comment: Schuch et al. (2021) report 3 unrelated individuals with bi-allelic variants in FARSA. Identified through WES and variants segregated with disease. Functional evidence was obtained with reduced FARS1 enzyme activity levels in fibroblasts or EBV-transformed lymphoblastoid cell lines (EBV-LCLs) of patients. Common to all was a chronic interstitial lung disease starting early in life and characterized by bilateral ground-glass opacification on HR-CT, and cholesterol pneumonitis in lung histology. Additional abnormalities in other organ systems include liver disease, neurological manifestations, and growth restriction.; Changed rating: GREEN; Changed publications: 31355908, 33598926; Changed phenotypes: Rajab interstitial lung disease with brain calcifications 2, MIM# 619013 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7986 | RELN |
Ee Ming Wong edited their review of gene: RELN: Added comment: - Six affected individuals carrying missense variants in RELN including 1. Two individuals with compound heterozygous variants - One of the variants has 26 homozygotes in gnomAD and therefore pathogenicity of this variant is in question - LoF demonstrated for three of the variants (reduced RELN secretion), except for p.Y1821H which demonstrated an apparently increased RELN secretion (GoF) 2. Two brothers carrying the maternally inherited variant (mother apparently healthy) - LoF demonstrated for these variants 3. Two individuals de novo for RELN variants - Dominant negative demonstrated for these variants where secretion of WT-RELN was impaired when co-transfected with mutant constructs in HEK293T cells; Changed rating: AMBER; Changed publications: Riva et al bioRxiv (pre-print, not peer-reviewed); Changed phenotypes: Pachygyria, Polymicrogyria, Heterotopia; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7712 | NSF | Zornitza Stark Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, MIM# 619340; Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7711 | NSF | Zornitza Stark edited their review of gene: NSF: Changed phenotypes: Developmental and epileptic encephalopathy 96, MIM# 619340, Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7605 | SPTLC1 | Zornitza Stark Phenotypes for gene: SPTLC1 were changed from to Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7602 | SPTLC2 | Zornitza Stark Phenotypes for gene: SPTLC2 were changed from to Neuropathy, hereditary sensory and autonomic, type IC, 613640; MONDO:0013337; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5860 | GSTO1 | Zornitza Stark Phenotypes for gene: GSTO1 were changed from to Deficiency of Human Glutathione Transferase Omega 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5857 | GSTO1 | Elena Savva reviewed gene: GSTO1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 21106529; Phenotypes: Deficiency of Human Glutathione Transferase Omega 1; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5739 | ST3GAL5 | Zornitza Stark Phenotypes for gene: ST3GAL5 were changed from to Salt and pepper developmental regression syndrome 609056; GM3 synthase deficiency, MONDO:0018274; Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5736 | ST3GAL5 | Zornitza Stark reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23436467, 22990144, 15502825, 27232954, 30691927, 30688114, 30576498; Phenotypes: Salt and pepper developmental regression syndrome 609056, GM3 synthase deficiency, MONDO:0018274, Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4872 | SHMT2 |
Zornitza Stark gene: SHMT2 was added gene: SHMT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly Review for gene: SHMT2 was set to GREEN Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs. Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones. SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes. While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect. The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4807 | ALG14 | Zornitza Stark changed review comment from: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation; to: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation. The three OMIM disorders may represent a spectrum of severity for CDG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3732 | FAM50A |
Zornitza Stark gene: FAM50A was added gene: FAM50A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Review for gene: FAM50A was set to GREEN Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3687 | PSAT1 | Zornitza Stark Phenotypes for gene: PSAT1 were changed from to Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3684 | PSAT1 | Elena Savva reviewed gene: PSAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32077105; Phenotypes: ?Phosphoserine aminotransferase deficiency 610992, Neu-Laxova syndrome 2 616038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3653 | CRY1 |
Ee Ming Wong gene: CRY1 was added gene: CRY1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRY1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRY1 were set to PMID: 28388406; PMID: 32538895 Phenotypes for gene: CRY1 were set to Attention deficit/hyperactivity disorder (ADHD); Delayed sleep phase disorder (DSPD), Penetrance for gene: CRY1 were set to Incomplete Review for gene: CRY1 was set to GREEN gene: CRY1 was marked as current diagnostic Added comment: - Splice variants identified in 7 families with ADHD and DSPD - Gain of function suggested for CRY1Δ11 (PMID: 28388406) - Loss of function suggested for CRY1Δ6 (HEK293T cells transfected with a Per1::Luc reporter plasmid showed reduced repressor activity compared to WT and CRY1Δ11) Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3578 | OXCT1 | Zornitza Stark Phenotypes for gene: OXCT1 were changed from to Succinyl CoA:3-oxoacid CoA transferase deficiency MIM#245050 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3575 | OXCT1 | Zornitza Stark reviewed gene: OXCT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25778941, 10964512, 8751852, 23420214; Phenotypes: Succinyl CoA:3-oxoacid CoA transferase deficiency MIM#245050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2955 | VWA3B |
Bryony Thompson gene: VWA3B was added gene: VWA3B was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: VWA3B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA3B were set to 26157035 Phenotypes for gene: VWA3B were set to Spinocerebellar ataxia, autosomal recessive 22 MIM#616948 Review for gene: VWA3B was set to AMBER Added comment: A homozygous missense variant was identified in 3 brothers from a single consanguineous Japanese family with autosomal recessive cerebellar ataxia. Transfection of the mutant VWA3B protein into several different cultured cell lines resulted in decreased cell viability. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2932 | DNAH6 |
Elena Savva gene: DNAH6 was added gene: DNAH6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNAH6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAH6 were set to PMID: 26918822 Phenotypes for gene: DNAH6 were set to Heterotaxy, Azoospermia Review for gene: DNAH6 was set to AMBER Added comment: PMID: 26918822 - zebrafish model has disrupted motile cilia and cilia length, with some body axis defects within embryos. Transfected human cells also had defective motile cilia and cilia width. Two patients with heterotaxy, one homozygous (missense), the other heterozygous (missense), but the heterozygous carrier has an additional known PCD mutation in DNA1. Summary: 1 convincing patient with animal model Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2814 | LRRC56 |
Elena Savva gene: LRRC56 was added gene: LRRC56 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: LRRC56 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRC56 were set to PMID: 30388400 Phenotypes for gene: LRRC56 were set to Ciliary dyskinesia, primary, 39 618254 Added comment: PMID: 30388400 - used protist null model to show abnormal ciliary beatings, replicated the phenotype when the protist was transfected with mutant allele observed in a patient. 3 unrelated families reported with either homozygous splice, missense or chet (nonsense/splice). Patients exhibited phenotypes including chronic respiratory/ear infections, situs inversus Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2587 | KIF12 | Zornitza Stark Phenotypes for gene: KIF12 were changed from Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT) to Cholestasis; High Gamma-Glutamyltransferase (GGT) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2580 | KIF12 |
Ee Ming Wong gene: KIF12 was added gene: KIF12 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIF12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF12 were set to PMID: 30250217; 30976738 Phenotypes for gene: KIF12 were set to Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT) Review for gene: KIF12 was set to AMBER gene: KIF12 was marked as current diagnostic Added comment: > 3 unrelated families,but they are all consanguineous families Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2377 | GSX2 |
Elena Savva gene: GSX2 was added gene: GSX2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GSX2 were set to PMID: 31412107 Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646 Review for gene: GSX2 was set to GREEN Added comment: PMID: 31412107 - 2 unrelated patients with homozygous mutations (nonsense, missense). Functional analysis of the missense in transfected HeLa cells demonstrated protein mislocalization and protein expression. Downstream gene expression was also reduced by both mutations. Summary: GREEN - 2 patients and functional evidence Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2372 | ACKR3 |
Elena Savva gene: ACKR3 was added gene: ACKR3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACKR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACKR3 were set to PMID: 3121183 Phenotypes for gene: ACKR3 were set to Oculomotor synkinesis Review for gene: ACKR3 was set to AMBER Added comment: No phenotype currently listed in OMIM PMID: 3121183 - 1 family (3 siblings and a cousin) with congenital ptosis and oculomotor synkinesis. Mouse model reciprocated the phenotype. Functional assay using transfected HEK293 cells show protein mislocalization and lower binding affinity Emerging gene-disease association Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1673 | FUT6 | Zornitza Stark Phenotypes for gene: FUT6 were changed from to Fucosyltransferase 6 deficiency, MIM# 613852 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1671 | FUT6 | Zornitza Stark reviewed gene: FUT6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fucosyltransferase 6 deficiency, MIM# 613852; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1255 | NSF | Zornitza Stark Marked gene: NSF as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1255 | NSF | Zornitza Stark Gene: nsf has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1255 | NSF | Zornitza Stark Classified gene: NSF as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1255 | NSF | Zornitza Stark Gene: nsf has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1254 | NSF |
Zornitza Stark gene: NSF was added gene: NSF was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NSF were set to 31675180 Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability Review for gene: NSF was set to AMBER Added comment: Two individuals reported with de novo missense variants in this gene. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1252 | KAT8 |
Zornitza Stark gene: KAT8 was added gene: KAT8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KAT8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Intellectual disability; seizures; autism; dysmorphic features Review for gene: KAT8 was set to GREEN Added comment: Eight unrelated individuals reported with de novo variants in this gene and a mouse model. All variants missense, in the chromobarrel domain or the acetyltransferase domain; three individuals had the same variant p.Tyr90Cys . One more individual reported with bi-allelic variants: one missense and one frameshift; carrier parents were normal suggesting that may be haploinsuffiency is not the mechanism. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1077 | LIPT1 | Zornitza Stark Phenotypes for gene: LIPT1 were changed from to Lipoyltransferase 1 deficiency, MIM#616299; Leigh-like presentation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1054 | LIPT1 | Elena Savva reviewed gene: LIPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoyltransferase 1 deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.780 | SLC9A7 |
Zornitza Stark gene: SLC9A7 was added gene: SLC9A7 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: SLC9A7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SLC9A7 were set to 30335141 Phenotypes for gene: SLC9A7 were set to Intellectual developmental disorder, X-linked 108; OMIM #301024 Review for gene: SLC9A7 was set to AMBER Added comment: 6 males from 2 unrelated families with hemizygous missense mutation in the SLC9A7 gene. The mutation segregated with the disorder in the family. In vitro functional expression studies in CHO cells (AP-1 cells) showed that the mutation caused decreased levels of protein expression and reduced oligosaccharide maturation/glycosylation compared to wildtype, indicating impaired posttranslational processing. Subcellular localization studies indicated that protein trafficking was unaffected by the mutation. However, examination of the trans-Golgi compartment suggested a gain-of-function effect and a perturbation of glycosylation of secretory cargo. Serum transferrin studies in 1 patient suggested a glycosylation defect. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||