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

Abstract

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known <i>FANC</i> genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated <i>FANC</i> genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. <i>FANCA</i> and <i>FANCG</i> pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one <i>FANCA</i> and two <i>FANCG</i> hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). <i>FANCB</i> was the third most common complementation group and only one <i>FANCC</i> case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing <i>FANC</i> gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.