RESUMEN
BACKGROUND: Cystathionine beta-synthase (CBS) deficiency is the most common cause of homocystinuria. However, no data are available concerning the molecular basis of this disease in Brazilian populations. METHODS: We studied 14 Brazilian patients from 11 unrelated families using a combined screening approach, involving restriction analysis, single-strand conformational polymorphism (SSCP) scanning, and sequencing. RESULTS: All patients presented homocysteine levels higher than 200 mumol/l before the beginning of treatment. The most common CBS gene mutations, p.G307S (c.919G > A) and p.I278T (c.833T > C), were evaluated and the allele c.919A was not found. One allele with the c.844 ins68 (4.5%) in the CBS gene was found. Three families (6 patients) presented the allele c.833 C (13.6%), without the insertion in the heterozygous state. SSCP scanning and sequencing showed 3 alleles p.T191M (13.64%) in 2 families. One allele with a novel mutation was found in exon 4 (c.168T > A) of the CBS gene (4.5%). We also analyzed c.677C > T and c.1298A > C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the 2756A > G polymorphism in the methionine synthase (MTR) gene. The frequencies of mutated alleles were: 50% c.677T and 18.2% c.1298C for MTHFR, and 27.3% c.2756G for MTR. CONCLUSION: In spite of the high level of racial mixing in the country, Brazilian homocystinuric patients did not present a high prevalence of the most common mutations described in the literature.
Asunto(s)
Homocistinuria/sangre , Homocistinuria/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Adolescente , Adulto , Alelos , Brasil , Niño , Preescolar , Cistationina betasintasa/deficiencia , Cistationina betasintasa/genética , Exones/genética , Femenino , Homocisteína/sangre , Homocistinuria/enzimología , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación/genética , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Hereditary breast cancer (HBC) accounts for 5-10% of breast cancer cases and it significantly increases the lifetime risk of cancer. Our objective was to evaluate the sociodemographic variables, family history of cancer, breast cancer (BC) screening practices and the risk profile of cancer affected or asymptomatic at-risk women that undergo genetic counseling for hereditary breast cancer in public Brazilian cancer genetics services. Estimated lifetime risk of BC was calculated for asymptomatic women using the Gail and Claus models. The majority of women showed a moderate lifetime risk of developing BC, with an average risk of 19.7% and 19.9% by the Gail and Claus models, respectively. The average prior probability of carrying a BRCA1/2 gene mutation was 16.7% and overall only 32% fulfilled criteria for a hereditary breast cancer syndrome as assessed by family history. We conclude that a significant number of individuals at high-risk for HBC syndromes may not have access to the benefits of cancer genetic counseling in these centers. Contributing factors may include insufficient training of healthcare professionals, disinformation of cancer patients; difficult access to genetic testing and/or resistance in seeking such services. The identification and understanding of these barriers is essential to develop specific strategies to effectively achieve cancer risk reduction in this and other countries were clinical cancer genetics is not yet fully established.