Cytopenia - NOT Fanconi anaemia
Gene: RPA1
The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 8:15 a.m. | Last Modified: 1 Feb 2023, 8:15 a.m.
Panel Version: 2.3
Comment on list classification: Despite the heterogenous phenotypes observed, there are sufficient cases (3) with hematopoietic manifestations to warrant a green rating on this panel at the next GMS review.Created: 6 Apr 2022, 10:55 a.m. | Last Modified: 6 Apr 2022, 10:55 a.m.
Panel Version: 1.61
Sharma et al., 2022 (PMID: 34767620) report four unrelated individuals with three distinct heterozygous GOF variants in the RPA1 gene. Clinical presentation was variable but mainly affecting the hematopoietic or pulmonary systems. Patient 1 presented with pancytopenia, hypoplastic bone marrow, and the classic DKC triad; Patient 2 developed myelodysplastic syndrome (MDS) with excess blasts, as well as mildly restrictive lung disease which progressed to pulmonary fibrosis (PF) following several HSCT-related complications; Patient 3 had adult-onset idiopathic PF with a positive family history (although segregation analysis was not possible); Patient 4 presented at birth with T- and B-cell lymphopenia and hypogammaglobulinemia. All probands demonstrated short telomere lengths.Created: 6 Apr 2022, 10:45 a.m. | Last Modified: 6 Apr 2022, 10:45 a.m.
Panel Version: 1.58
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
Publications
4 cases with gain of function mutations with "including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations." described in
https://doi.org/10.1182/blood.2021011980
Sources: LiteratureCreated: 12 Nov 2021, 7:21 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations.
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag Q2_22_rating was removed from gene: RPA1.
Source Expert Review Green was added to RPA1. Source NHS GMS was added to RPA1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: rpa1 has been classified as Amber List (Moderate Evidence).
Tag Q2_22_rating tag was added to gene: RPA1.
Penetrance for gene RPA1 was set from to unknown
Publications for gene: RPA1 were set to
Phenotypes for gene: RPA1 were changed from bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations. to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
gene: RPA1 was added gene: RPA1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RPA1 were set to bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations. Penetrance for gene: RPA1 were set to unknown Mode of pathogenicity for gene: RPA1 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: RPA1 was set to GREEN