Five Novel Deleterious Variants in FANCA, FANCF and FANCG Identified in Pakistani Fanconi Anemia Families Using Exome Sequencing

Abstract Background Fanconi anemia (FA), a cancer-prone inherited bone marrow failure syndrome associated with characteristic dysmorphology is primarily caused by autosomal recessive inheritance of pathogenic germline variants in any of 22 different DNA repair genes. Pathogenic variants in FANCA are the most frequent cause, followed by FANCC and FANCG. There are limited data on the specific molecular causes of FA in different ethnic groups. Methods We evaluated 19 patients with FA undergoing hematopoietic cell transplantation evaluation, from 17 families in Pakistan with exome sequencing and copy number variant analysis. To accompany these efforts, we reviewed the literature and curated a list of variants reported in patients with FA from South Asia and the Middle East.Results The genetic causes for disease were identified in 14 families: 7 FANCA, 2 FANCC, 1 FANCF, 2 FANCG, and 2 FANCL. Homozygous and compound heterozygous variants were present in 12 and 2 families, respectively. Nine families carried variants previously reported as pathogenic, including two families with the South Asian FANCL founder variant. We also identified five novel likely deleterious variants in FANCA, FANCF, and FANCG in affected patients. Conclusions Our study supports the importance of determining the genomic landscape of FA in diverse populations, in order to improve understanding of FA etiology and assist in the counseling of families.