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Red cell disorders v1.22 SLC19A1 Zornitza Stark edited their review of gene: SLC19A1: Added comment: PMID: 36745868 report two distantly related patients (last common ancestor 5 generations prior) with the same homozygous missense variant, G348R. The variant is absent from gnomAD, although the residue is not conserved in mammals. Both patients experienced severe recurrent infection, neurologic and hematologic disorders, and gastroenteropathy. Functional studies on patient lymphocytes were consistent with reduced transporter activity.

PMID: 36517554 report two cousins with immunodeficiency with the same G348R variant as above. Functional studies on patient cells supported loss of transporter function. The patient’s symptoms ameliorated, and hematological and immunological tests normalized in the 2nd month of folinic acid supplementation.

Phenotypes not entirely consistent, homozygous variants.; Changed rating: AMBER; Changed publications: 32276275, 36745868, 36517554; Changed phenotypes: Megaloblastic anemia, folate-responsive, MIM# 601775
Red cell disorders v1.20 POLE Lilian Downie gene: POLE was added
gene: POLE was added to Red cell disorders. Sources: Literature
Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLE were set to PMID: 37833059
Phenotypes for gene: POLE were set to MONDO:0002254 syndromic disease
Review for gene: POLE was set to RED
Added comment: 2 sibs with compound heterozygous high impact variants with combined features of previously reported phenotypes (IMAGe and FILS) with this gene and new feature of congenital anaemia that evolved into myelodysplastic syndrome. Both had growth failure and epicanthic folds. Some functional work on human cells and a fish model to provide evidence of role in haematopoiesis.
Sources: Literature
Red cell disorders v1.16 RHCE Zornitza Stark gene: RHCE was added
gene: RHCE was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: RHCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHCE were set to 9657766; 16271106; 25413218
Phenotypes for gene: RHCE were set to Rh-null disease, amorph type, MIM# 617970
Review for gene: RHCE was set to GREEN
Added comment: The RH-null phenotype designates rare individuals whose red blood cells lack all Rh antigens. Clinically, Rh-null patients present mild to moderate hemolytic anemia; cells exhibit characteristic morphologic and functional abnormalities including spherocytosis, stomatocytosis, and diminished lifespan. Multiple families reported.
Sources: Expert list
Red cell disorders v1.15 RACGAP1 Zornitza Stark gene: RACGAP1 was added
gene: RACGAP1 was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: RACGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RACGAP1 were set to 34818416
Phenotypes for gene: RACGAP1 were set to Anaemia, congenital dyserythropoietic, type IIIb, autosomal recessive 619789
Review for gene: RACGAP1 was set to RED
Added comment: Single affected individual reported.
Sources: Expert list
Red cell disorders v1.11 KIF23 Zornitza Stark edited their review of gene: KIF23: Added comment: Second individual reported, elongation variant.; Changed rating: AMBER; Changed phenotypes: Anaemia, congenital dyserythropoietic, type IIIA 105600
Red cell disorders v1.3 AMMECR1 Zornitza Stark gene: AMMECR1 was added
gene: AMMECR1 was added to Red cell disorders. Sources: Expert Review
Mode of inheritance for gene: AMMECR1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AMMECR1 were set to 27811305; 28089922; 29193635
Phenotypes for gene: AMMECR1 were set to Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis, MIM# 300990
Review for gene: AMMECR1 was set to GREEN
Added comment: More than 5 unrelated individuals reported with midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis.Anaemia is sometimes present. Some individuals may show mild early motor or speech delay, but cognition is normal. However, onset is in early childhood.
Sources: Expert Review
Red cell disorders v1.1 HSCB Zornitza Stark gene: HSCB was added
gene: HSCB was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: HSCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSCB were set to 32634119
Phenotypes for gene: HSCB were set to Anaemia, sideroblastic, 5 619523
Review for gene: HSCB was set to AMBER
Added comment: Single individual reported with compound heterozygous variants in this gene. Good functional data including animal model.
Sources: Expert list
Red cell disorders v0.182 NHP2 Zornitza Stark changed review comment from: Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Clinical manifestations include mucocutaneous abnormalities, bone marrow failure, and an increased predisposition to cancer, among other variable features. Three unrelated families reported.; to: Pancytopaenia.
Red cell disorders v0.170 DKC1 Zornitza Stark changed review comment from: Dyskeratosis congenita is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. It is characterized by short telomeres. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, and learning difficulties. Males may have testicular atrophy. Predisposition to malignancy is an important feature.

Hoyeraal-Hreidarsson syndrome (HHS) refers to a clinically severe variant of DKC that is characterized by multisystem involvement and early onset in utero. Patients with HHS show intrauterine growth retardation, microcephaly, delayed development, and bone marrow failure resulting in immunodeficiency, cerebellar hypoplasia, and sometimes enteropathy. Death often occurs in childhood.

PMID: 25940403, at least 13 of the variants associated with dyskeratosis congenita were also reported to cause HHS: P10L, I38T, T66A, T67I, H68Q, H68Y, S121G, R158W, K314R, A353V, R378Q, A386T and IVS12+1, so NOT only variants in exon 11. Two mutations were only found in HH, T49M and S304N.; to: Pancytopaenia rather than a red cell disorder.
Red cell disorders v0.158 SH2B3 Zornitza Stark gene: SH2B3 was added
gene: SH2B3 was added to Red cell disorders. Sources: Expert Review
somatic tags were added to gene: SH2B3.
Mode of inheritance for gene: SH2B3 was set to Other
Publications for gene: SH2B3 were set to 34349782; 23812944; 20843259
Phenotypes for gene: SH2B3 were set to Erythrocytosis, somatic, MIM# 133100
Mode of pathogenicity for gene: SH2B3 was set to Other
Review for gene: SH2B3 was set to AMBER
Added comment: Limited reports, variants appear to be somatic.
Sources: Expert Review
Red cell disorders v0.156 JAK2 Zornitza Stark gene: JAK2 was added
gene: JAK2 was added to Red cell disorders. Sources: Expert Review
somatic tags were added to gene: JAK2.
Mode of inheritance for gene: JAK2 was set to Other
Publications for gene: JAK2 were set to 27389715
Phenotypes for gene: JAK2 were set to Erythrocytosis, somatic, 133100
Mode of pathogenicity for gene: JAK2 was set to Other
Review for gene: JAK2 was set to AMBER
Added comment: There is limited evidence to support an association of JAK2 variants with hereditary/congenital erythrocytosis. Typically, variants are somatic/acquired; and to date, only one report has described a patient with germline compound het variants (p.E846D and p.R1063H) in JAK2, who exhibited polyclonal erythrocytosis and megakaryocytic atypia but normal platelet number (PMID:27389715).

GoF somatic variants in this gene are also associated with polycythaemia vera (PV), particularly p.V617F, but also with reports of some familial clustering due to inheritance of the JAK2 46/1 predisposition haplotype.

Amber rating due to the somatic nature of variants.
Sources: Expert Review
Red cell disorders v0.153 EPOR Zornitza Stark Marked gene: EPOR as ready
Red cell disorders v0.153 EPOR Zornitza Stark Gene: epor has been classified as Green List (High Evidence).
Red cell disorders v0.153 EPOR Zornitza Stark Classified gene: EPOR as Green List (high evidence)
Red cell disorders v0.153 EPOR Zornitza Stark Gene: epor has been classified as Green List (High Evidence).
Red cell disorders v0.152 EPOR Zornitza Stark gene: EPOR was added
gene: EPOR was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: EPOR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPOR were set to 8506290; 9292543; 30507031; 33061762
Phenotypes for gene: EPOR were set to [Erythrocytosis, familial, 1], MIM# 133100
Review for gene: EPOR was set to GREEN
Added comment: Well established gene-disease association.
Sources: Expert list
Red cell disorders v0.151 EPO Zornitza Stark Marked gene: EPO as ready
Red cell disorders v0.151 EPO Zornitza Stark Gene: epo has been classified as Green List (High Evidence).
Red cell disorders v0.151 EPO Zornitza Stark Classified gene: EPO as Green List (high evidence)
Red cell disorders v0.151 EPO Zornitza Stark Gene: epo has been classified as Green List (High Evidence).
Red cell disorders v0.150 EPO Zornitza Stark gene: EPO was added
gene: EPO was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: EPO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPO were set to 27651169; 29514032; 32130275; 20700488; 30507031; 28283061
Phenotypes for gene: EPO were set to Erythrocytosis, familial, 5, MIM# 617907; Diamond-Blackfan anaemia-like, MIM# 617911
Review for gene: EPO was set to GREEN
Added comment: More than 5 unrelated families reported, though note one paper has been retracted.

Single family with bi-allelic variants and a DBA phenotype.
Sources: Expert list
Red cell disorders v0.146 EGLN1 Zornitza Stark gene: EGLN1 was added
gene: EGLN1 was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: EGLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EGLN1 were set to 19092153; 16407130; 17579185
Phenotypes for gene: EGLN1 were set to Erythrocytosis, familial, 3, MIM# 609820
Review for gene: EGLN1 was set to GREEN
Added comment: At least 3 unrelated families reported.
Sources: Expert list
Red cell disorders v0.144 BPGM Zornitza Stark gene: BPGM was added
gene: BPGM was added to Red cell disorders. Sources: Expert list
Mode of inheritance for gene: BPGM was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BPGM were set to 1421379; 27651169; 25015942
Phenotypes for gene: BPGM were set to Erythrocytosis, familial, 8, MIM# 222800
Review for gene: BPGM was set to AMBER
Added comment: Mixture of mono-allelic and bi-allelic variants reported, MOI uncertain.
Sources: Expert list
Red cell disorders v0.81 HBD Zornitza Stark Phenotypes for gene: HBD were changed from Thalassemia due to Hb Lepore; Thalassemia,delta; Thalassemiadue to HbLepore; 141749 Delta-beta thalassaemia, thalassaemia due to Hb Lepore; Thalassemia, delta to Thalassaemia, delta-; Thalassaemia due to Hb Lepore
Red cell disorders v0.80 HBD Zornitza Stark reviewed gene: HBD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thalassaemia, delta-, Thalassaemia due to Hb Lepore; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Red cell disorders v0.62 GLRX5 Zornitza Stark changed review comment from: Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit. At least three unrelated individuals reported.; to: Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anaemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit. At least three unrelated individuals reported.
Red cell disorders v0.40 COX4I2 Zornitza Stark changed review comment from: Missense variant reported in 4 affected individuals from 2 consanguineous families however the variant is also found in the gnomAD database (186 hets; 3 homs).; to: Missense variant reported in 4 affected individuals from 2 consanguineous families however the variant is also found in the gnomAD database (186 hets; 3 homs). Note no other variants reported in this gene since original report in 2009. All variants submitted to ClinVar are VOUS/LB/B.
Red cell disorders v0.33 CD59 Zornitza Stark changed review comment from: Infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Intermittent episodes of haemolysis.; to: Infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Intermittent episodes of haemolysis.

More than 5 unrelated families reported.
Red cell disorders v0.18 ADA2 Zornitza Stark changed review comment from: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits. Some affected individuals have immunodeficiency.

At least 10 unrelated families reported, the p.Gly47Arg variant is a common founder variant in the Jewish population.; to: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits. Some affected individuals have immunodeficiency.

At least 10 unrelated families reported, the p.Gly47Arg variant is a common founder variant in the Jewish population.

Anaemia is a reported feature.
Red cell disorders v0.5 SLC19A1 Zornitza Stark gene: SLC19A1 was added
gene: SLC19A1 was added to Rare anaemia_GEL. Sources: Expert list
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275
Phenotypes for gene: SLC19A1 were set to Megaloblastic anemia, folate-responsive, MIM# 601775
Review for gene: SLC19A1 was set to RED
Added comment: Single individual reported with in-frame deletion, some functional data.
Sources: Expert list
Red cell disorders v0.3 VPS4A Zornitza Stark gene: VPS4A was added
gene: VPS4A was added to Rare anaemia_GEL. Sources: Literature
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to 33186543; 33186545
Phenotypes for gene: VPS4A were set to syndromic congenital dyserythropoietic anaemia
Mode of pathogenicity for gene: VPS4A was set to Other
Review for gene: VPS4A was set to GREEN
Added comment: 6 of 9 reported individuals had anaemia as part of a syndromic neurodevelopmental disorder.
Sources: Literature
Red cell disorders v0.1 HBD Zornitza Stark Added phenotypes Thalassemia due to Hb Lepore; Thalassemia,delta; Thalassemiadue to HbLepore; 141749 Delta-beta thalassaemia, thalassaemia due to Hb Lepore; Thalassemia, delta for gene: HBD
Red cell disorders v0.0 HBD Zornitza Stark gene: HBD was added
gene: HBD was added to Rare anaemia_GEL. Sources: London South GLH,North West GLH,Expert Review Green,Wessex and West Midlands GLH,NHS GMS,Yorkshire and North East GLH
Mode of inheritance for gene: HBD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HBD were set to 27630894; 25490067
Phenotypes for gene: HBD were set to Thalassemiadue to HbLepore; Thalassemia due to Hb Lepore; 141749 Delta-beta thalassaemia, thalassaemia due to Hb Lepore; Thalassemia,delta; Thalassemia, delta