Non-invasive assessment of early embryonic somatic mosaicism and hypermutation phenomenon in patients with Fanconi anemia
The pathogenesis of congenital malformations, early progressive bone marrow failure, and carcinogenesis, including myelodysplastic syndrome, acute myeloid leukemia, and solid tumors, in patients with Fanconi anemia (FA) remains poorly understood. Recently, we described a rare hypermutator phenotype phenomenon in an individual with FA complementation group O characterized by 830 apparent de novo mosaic SNVs and 21 de novo mosaic indels interpreted as early postzygotic events due to biallelic RAD51C variants and an impaired replicative repair process. To further investigate the hypermutator phenotype phenomenon in FA during early human embryogenesis up to 5th postzygotic mitotic division, we non-invasively study somatic mosaicism in individuals with FANCA, FANCD1/BRCA2, FANCS/BRCA1, and FANCT/UBE2T using family trio short read whole-genome sequencing with 300x coverage. We findan increased burden of SNVs/indels in FANCD1/BRCA2 and structural variants in FANCS/BRCA1. Our findings indicate that hypermutation and somatic mosaicism are recurrent features in selected FA complementation groups and different genomic outcomes arise mainly due to deficiency in homologous recombination (HR) during repair of double-strand breaks rather than by defective FA proteins outside HR. Moreover, deficiencies in different HR proteins result in various genomic outcomes.
The pathogenesis of congenital malformations, early progressive bone marrow failure, and carcinogenesis, including myelodysplastic syndrome, acute myeloid leukemia, and solid tumors, in patients with Fanconi anemia (FA) remains poorly understood. Recently, we described a rare hypermutator phenotype phenomenon in an individual with FA complementation group O characterized by 830 apparent de novo mosaic SNVs and 21 de novo mosaic indels interpreted as early postzygotic events due to biallelic RAD51C variants and an impaired replicative repair process. To further investigate the hypermutator phenotype phenomenon in FA during early human embryogenesis up to 5th postzygotic mitotic division, we non-invasively study somatic mosaicism in individuals with FANCA, FANCD1/BRCA2, FANCS/BRCA1, and FANCT/UBE2T using family trio short read whole-genome sequencing with 300x coverage. We findan increased burden of SNVs/indels in FANCD1/BRCA2 and structural variants in FANCS/BRCA1. Our findings indicate that hypermutation and somatic mosaicism are recurrent features in selected FA complementation groups and different genomic outcomes arise mainly due to deficiency in homologous recombination (HR) during repair of double-strand breaks rather than by defective FA proteins outside HR. Moreover, deficiencies in different HR proteins result in various genomic outcomes.
Baylor College of Medicine