Multi-lineage natural gene therapy mediated by embryonic triploid mosaicism in the context of Fanconi anaemia

Abstract

Fanconi anemia is a rare inherited bone marrow failure syndrome caused by inactivation of genes in the Fanconi anemia/BRCA DNA repair pathway. We report a patient with X-linked Fanconi anemia, and atypical physical features whose genetic diagnosis was initially inconclusive. Over time, his bone marrow karyotype shifted from diploid (46,XY) to triploid (69,XXY). The triploid cells lacked the Fanconi anemia cellular phenotype, enabling sustained hematopoiesis and providing an unexpected route to phenotypic rescue. Genomic analysis indicated early post-zygotic incorporation of the second polar body as the triploid origin. These findings suggest that the selective advantage of restored DNA repair in hematopoietic stem cells, outweigh the potentially deleterious effects of triploidy.