Pulmonary fibrosis familial

Gene: RPA1

I don't know

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

• 34767620

Green List (high evidence)

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: Literature

Created: 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