Abstract
BACKGROUND: Fanconi anemia (FA) is a predominantly autosomal recessive disease with wide genetic heterogeneity resulting from mutations in several DNA repair pathway genes. To date, 21 genetic subtypes have been identified. We aimed to identify the FA genetic subtypes in the Brazilian population and to develop a strategy for molecular diagnosis applicable to routine clinical use. METHODS: We screened 255 patients from Hospital de Clínicas, Universidade Federal do Paraná for 11 common FA gene mutations. Further analysis by multiplex ligation-dependent probe amplification (MLPA) for FANCA and Sanger sequencing of all coding exons of FANCA, -C, and -G was performed in cases who harbored a single gene mutation. RESULTS: We identified biallelic mutations in 128/255 patients (50.2%): 89, 11, and 28 carried FANCA,FANCC, and FANCG mutations, respectively. Of these, 71 harbored homozygous mutations, whereas 57 had compound heterozygous mutations. In 4/57 heterozygous patients, both mutations were identified by the initial screening, in 51/57 additional analyses was required for classification, and in 2/57 the second mutation remained unidentified. We found 52 different mutations of which 22 were novel. CONCLUSION: The proposed method allowed genetic subtyping of 126/255 (49.4%) patients at a significantly reduced time and cost, which makes molecular diagnosis of FA Brazilian patients feasible.