Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey

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 inFANCA were found responsible in 75%,FANCC,FANCE,FANCJ/BRIP1,FANCL in 5%, andFANCD1/BRCA2 andFANCN/PALB2 in 2.5% of the subjects. Altogether, 25 different variants in 7 different FA genes, including 10 novel mutations inFANCA,FANCN/PALB2,FANCE, andFANCJ/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 novoFANCD1/BRCA2 and paternally inheritedFANCN/PALB2 pathogenic alleles at first glance suggested a digenic inheritance, because the presence of a second pathogenic variant in the unexamined regions ofFANCD1/BRCA2 andFANCN/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.Mol Syndromol
Source: Molecular Syndromology - Category: Molecular Biology Source Type: research