Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients

Fanconi anemiais a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies, resulting from mutations in one of the 22 known FANCgenes. The number of Japanese Fanconi anemiapatients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANCgenes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCAand FANCGpathogenic variants accounted for the disease in 58% and 25% of Fanconi anemiapatients, respectively. We found one FANCAand two FANCGhot spot mutations, which exist at low percentages (0.04-0.1%) in the whole-genome reference panel of 3554 Japanese individuals (Tohoku Medical Megabank). FANCBwas the third most common complementation groupand only one FANCC case was identified in our series. Based on the data from Tohoku Medical Megabank, we estimate that ~2.6% of Japanese are carriers of disease-causing FANCgene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemiapatients to date and the results will be useful for future clinical management.