Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation

Abstract

Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

Características clínicas de pacientes com anemia de Fanconi

“…Radial abnormalities may be unilateral or bilateral, and even those who have bilateral abnormalities usually present with a certain asymmetry, with their limbs showing different anomalies (27) . Radial anomalies, along with hematologic dysfunctions, were frequent in both groups of our study (with and without FA), and this finding may be related to the fact that it represents the main reasons that lead to suspicion o FA (3,5,6,11).…”

“…In addition, several different mutations have been identified in each one of these genes, which makes the disease even more genetically heterogeneous. The genes BRCA1 (OMIM 113705) (1) and BRCA2 (OMIM 600185) (1) are also associated with the abnormal DNA repair pathway in FA, and it has been recently found that FANCD1 and BRCA2 genes are actually the same gene (4,5,7,11) . Among the complementation groups, the most often mentioned is A (FANCA), reported in 57 to 65% of the cases (11) .…”

“…The genes BRCA1 (OMIM 113705) (1) and BRCA2 (OMIM 600185) (1) are also associated with the abnormal DNA repair pathway in FA, and it has been recently found that FANCD1 and BRCA2 genes are actually the same gene (4,5,7,11) . Among the complementation groups, the most often mentioned is A (FANCA), reported in 57 to 65% of the cases (11) . Despite major advances in the past decades regarding the molecular mechanisms involved in FA, a genotype-phenotype correlation has not been well defined.…”

“…Given the importance of identifying these patients and the lack of studies conducted in Brazil mainly focused on their clinical characteristics (10)(11)(12)(13)(14)(15) , the objective of the present study was to characterize the clinical profile of patients diagnosed with FA seen at a clinical genetics department.…”

Validation of Fanconi anemia complementation Group A assignment using molecular analysis

“…34 With more than 200 different mutations described thus far, the FANCA mutation spectrum is very heterogeneous. 2,12,30,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] Because of the presence of a large number of Alu repeat sequences within the FANCA gene, large intragenic deletions involving multiple exons have been reported to account for more than 40% of all FANCA mutations. 54,55 Because the majority of FA patients fall into complementation group FA-A, we initiated verification of accuracy of FA complementation assignment in this genetic subtype.…”