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| Mendeliome v1.4534 | RPA2 | Zornitza Stark Marked gene: RPA2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4534 | RPA2 | Zornitza Stark Gene: rpa2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4534 | RPA2 |
Zornitza Stark gene: RPA2 was added gene: RPA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPA2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: RPA2 were set to 41703052; 39231615 Phenotypes for gene: RPA2 were set to Telomere syndrome, MONDO:0100137, RPA2-related Review for gene: RPA2 was set to RED Added comment: PMID 41703052 reports a 6‑year‑old individual from a consanguineous family who is homozygous for the splice‑site variant c.409‑2A>G (p.Q136_K138del). The patient presented with early‑onset bone‑marrow failure, immunodeficiency, microcephaly, dysmorphic features and severely short telomeres. The heterozygous parents are asymptomatic carriers. Functional studies showed ~50% reduction of RPA2 protein, destabilization of the OB‑fold ssDNA‑binding groove, impaired telomere binding, severe telomere shortening, increased telomere variant repeats and chromosome end‑to‑end fusions, supporting a loss‑of‑function mechanism. PMID 39231615 reports 2 individuals from 2 unrelated families with a heterozygous missense variant c.767A>G (p.Y256C) presenting with adult‑onset telomere biology disorder characterized by pleuroparenchymal fibroelastosis/interstitial lung disease, short telomeres, bone‑marrow failure (macrocytic anemia, myelodysplastic syndrome), liver disease and osteoporosis. Variant is ultra‑rare (gnomAD v4 1 het) and predicted deleterious. Functional studies (RPE1 knock‑in cell lines, RFWD3 interaction and ubiquitination assays, ATR signaling, telomere length assays, and a mouse model lethal in homozygous state) demonstrate loss‑of‑function effects, supporting pathogenicity. Both patients acquired, in a subset of blood cells, somatic genetic rescue events in either POT1 genes or TERT promoters known to counteract the accelerated telomere shortening. Sources: Literature |
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