The FANCA gene in Japanese Fanconi anemia: Report of eight novel mutationsand analysis of sequence variability

Fanconi anemia (FA), an autosomal recessive disorder characterized by a pro gressive pancytopenia associated with congenital anomalies and high predisp osition to malignancies, is a genetically and clinically heterogeneous dise ase. At least eight complementation groups (FA-A to FA-H) have been identif ied with their relative prevalence varying among the ethnical backgrounds. Recently, responsible genes, FANCA and FANCC, have been cloned, This report describes mutations of the FANCA gene, which we studied by direct sequenci ng of cDNA with confirmation on genomic DNA in 15 unclassified Japanese FA patients. A total of 19 sequence alterations were identified, of which 10 ( six missense and four silent alterations) were likely to be nonpathogenic p olymorphism. The remaining nine alterations, of which eight were novel muta tions, were assumed to be pathogenic and consisted of two missense mutation s and seven mutations resulting in truncation of gene product, demonstratin g a wide allelic heterogeniety. The pathogenic mutations were found in 12 p atients (80%); they were either homozygous or compound heterozygous in 10 p atients, apparently heterozygous in two patients and none in three patients . We conclude that the sequence variability is intrinsic to the FANCA gene and that the relative prevalence of the FA-A subtype is unusually high in J apanese FA patients. Hum Mutat 13:237-244, 1999. (C) 1999 Wiley-Liss, Inc.