SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia

Roni Zemet, Haowei Du, Tomasz Gambin, James R. Lupski*, Pengfei Liu*, Paweł Stankiewicz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5 and 37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the hypothesis of a rare phenomenon of hypermutation. Eight-hundred-thirty apparent de novo SNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. The VAFs showed a bimodal distribution, with one component having an average VAF of 25% (range: 18.7–37.41%) (n = 446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range 9.55–18.69%) (n = 384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This ‘genome hypermutator phenomenon’ might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA. We propose that other FA groups should be investigated for genome-wide de novo variants.

Original languageEnglish
Pages (from-to)721-733
Number of pages13
JournalHuman Genetics
Issue number6
StatePublished - Jun 2023
Externally publishedYes


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