Genomic and clinical features of patients with germline heterozygous RPA1 variants
| Patient feature . | . | Germline mutation . | Disease feature . | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient | Sex | Age of onset (y) | RPA1 status | Exon | VAF% (TD) | Population database | CADD | Hematopoietic | Other | Recent status |
| P1 | F | 10 | c.718G>A, p.E240K de novo | 9 | 24%* (58) | Absent | 23.3 | Refractory cytopenia of childhood | Mucocutaneous triad Congenital eye anomaly† | No interventions Stable blood counts at age 28 y |
| P2 | F | 13 | c.680T>C, p.V227A | 8 | 51% (118) | gnomAD v3.1: 76078 genomes (1/152156 alleles) TOPMed freeze 8: 132345 genomes (2/264690 alleles)‡ | 26.9 | MDS with excess blasts | Mild restrictive lung disease Facial dysmorphism§ | HSCT Death at age 14 y (GVHD, infection, pulmonary fibrosis) |
| P3 | F | 58 | 53% (49) | BM not examined CBC normal | Familial pulmonary fibrosis‖ | Progression of pulmonary fibrosis on antifibrotics | ||||
| P4 | F | Birth | c.808A>G, p.T270A de novo | 10 | 41% (51) | Absent | 20.9 | BM not examined Low TRECs Lymphopenia Hypogammaglobulinemia | Prematurity (33 wk) | IgG replacement Stable CBC at age 3 y |
| Patient feature . | . | Germline mutation . | Disease feature . | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient | Sex | Age of onset (y) | RPA1 status | Exon | VAF% (TD) | Population database | CADD | Hematopoietic | Other | Recent status |
| P1 | F | 10 | c.718G>A, p.E240K de novo | 9 | 24%* (58) | Absent | 23.3 | Refractory cytopenia of childhood | Mucocutaneous triad Congenital eye anomaly† | No interventions Stable blood counts at age 28 y |
| P2 | F | 13 | c.680T>C, p.V227A | 8 | 51% (118) | gnomAD v3.1: 76078 genomes (1/152156 alleles) TOPMed freeze 8: 132345 genomes (2/264690 alleles)‡ | 26.9 | MDS with excess blasts | Mild restrictive lung disease Facial dysmorphism§ | HSCT Death at age 14 y (GVHD, infection, pulmonary fibrosis) |
| P3 | F | 58 | 53% (49) | BM not examined CBC normal | Familial pulmonary fibrosis‖ | Progression of pulmonary fibrosis on antifibrotics | ||||
| P4 | F | Birth | c.808A>G, p.T270A de novo | 10 | 41% (51) | Absent | 20.9 | BM not examined Low TRECs Lymphopenia Hypogammaglobulinemia | Prematurity (33 wk) | IgG replacement Stable CBC at age 3 y |
CADD, combined annotation-dependent depletion, pathogenicity threshold of 15; CBC, complete blood count; F, female; IgG, immunoglobulin G; TD, total depth; TRECs, T-cell receptor excision circles.
Confirmed germline in fibroblasts; decreased variant allele frequency (VAF) is due to UPD in blood cells.
Congenital persistent hyperplastic primary vitreous of the left eye requiring enucleation.
gnomAD v3.1 and TOPMed Bravo freeze 8 are population databases with population genome sequencing data.
Bilateral blepharophimosis, epicanthus inversus, eyelid ptosis, and thick eyebrows with high arch found in P2 and carrier father.
Pulmonary fibrosis diagnosed in 2 sisters of P3 (supplemental Figure 2). NM_002945.5 was used for variant nomenclature.