Pulmonary fibrosis familial
Gene: RPA1
Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerges.Created: 6 Apr 2022, 10:59 a.m. | Last Modified: 6 Apr 2022, 11 a.m.
Panel Version: 0.8
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
Gene: rpa1 has been classified as Amber List (Moderate Evidence).
gene: RPA1 was added gene: RPA1 was added to Pulmonary fibrosis familial. Sources: Literature Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPA1 were set to 34767620 Phenotypes for gene: RPA1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767 Penetrance for gene: RPA1 were set to Incomplete 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