Fanconi anemia (FA) is a rare multigenic chromosomal instability syndrome that predisposes patients to life-threatening bone marrow failure, congenital malformations, and cancer. Functional loss of interstrand cross-link (ICL) DNA repair system is held responsible, though the mechanism is not yet fully understood. The clinical and molecular findings of 20 distinct FA cases, ages ranging from perinatal stage to 32 years, are presented here. Pathogenic variants in FANCA were found responsible in 75%, FANCC , FANCE , FANCJ / BRIP1 , FANCL in 5%, and FANCD1 / BRCA2 and FANCN / PALB2 in 2.5% of the subjects. Altogether, 25 different variants in 7 different FA genes, including 10 novel mutations in FANCA , FANCN / PALB2 , FANCE, and FANCJ / BRIP1, were disclosed. Two compound heterozygous germline cases were mosaic for one allele, revealing that the incidence of reverse mutations may not be uncommon in FA. Another case with de novo FANCD1/BRCA2 and paternally inherited FANCN/PALB2 pathogenic alleles at first glance suggested a digenic inheritance, because the presence of a second pathogenic variant in the unexamined regions of FANCD1/BRCA2 and FANCN/PALB2 were exluded by sequencing and deletion/duplication analysis. A better understanding of the complexity of the FA genotype may provide further access to undiscovered ICL components and apparently dispensable cellular pathways where FA proteins may play important roles.
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