The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Homocysteine (Hcy) is converted to cysteine or is remethylated to methionine by methylenetetrahydrofolate reductase (MTHFR). MTHFR plays a central role in the metabolism of folate. Two common polymorphisms in the MTHFR gene (C677T and A1298C) have been described and studies suggest that these polymorphisms are positively associated with the occurrence of spina bifida (SB). Among Brazilians, the incidence of 677T allele homozygosity is 4%. We compared Hcy levels with the genotypes obtained for the mutations C677T and A1298C in the gene MTHFR. Levels of plasma Hcy were higher in children with SB than in controls (average 7.95 vs. 5.55 (micromol/L); P < 0.001). There was no significant difference in the levels of Hcy for these children's mothers and controls (average 7.76 vs. 8.36 (micromol/L); P = 0.27). Eighty one (61.8%) of the affected children were white and 50 (38.2%) were non-white. A similar ratio was observed in the mothers. In the control group, 51 children (40.5%) were white and 75 (59.5%) were non-white, and 52 mothers (41.3%) were white and 74 (58.7%) were non-white. There was no significant difference in the homozygous frequency for the mutated allele 677T among different racial groups. We obtained a prevalence of TT homozygosity of 10/131 (7.64%) in affected children and 13/126 (10.32%) in controls. With respect to the mutation A1298C, the homozygous prevalence for the wild allele was greater among non-white individuals than in white individuals both in case and control groups. Hyperhomocysteinemia is a risk factor for SB. However, in our population, the increase in plasma levels of Hcy is not explained by the presence of the homozygous TT. It is possible that low folic acid intake combined with other genetic factors plays a more important role in the cause of this disease.

Rearrangements in chromosome 19 are rare. Among the 35 patients with partial 19q trisomy described, only six have a breakpoint defined by array. The 19q duplication results in a variable phenotype, including dysmorphisms, intellectual disability and seizure. In a female patient, although G-banding at 550 band-resolution was normal, multiplex ligation-dependent probe amplification (MLPA) technique and genomic array showed a 10.6 Mb terminal duplication of chromosome 19q13. Fluorescent in situ hybridization (FISH) revealed that the duplicated region was attached to the short arm of chromosome 21 and silver staining showed four small acrocentrics with nucleolar organization region (NOR) activity, suggesting that the breakpoint in chromosome 21 was at p13. This is the first de novo translocation between 19q13.33 and 21p13 described in liveborn. The chromosome 19 is known to be rich in coding and non-coding regions, and chromosomal rearrangements involving this chromosome are very harmful. Furthermore, the 19q13.33→qter region is dense in pseudogenes and microRNAs, which are potent regulators of gene expression. The trisomic level of this region may contribute to deregulation of global gene expression, and consequently, may lead to abnormal development on the carriers of these rearrangements.

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-Background: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. Purpose: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. Method: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. Results: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. Conclusion: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/ phenotype correlations, guiding the implementation of mutation searching programs.KEY WORDS: Rett syndrome, genotype-phenotype correlation.correlação genótipo-fenótipo em pacientes brasileiras com síndrome de rett resumo -Introdução: A síndrome de Rett é uma grave doença do neurodesenvolvimento ligada ao X dominante, causada por mutações no gene MECP2. Objetivos: Identificar mutações de ponto no gene MECP2 e estabelecer uma correlação entre as principais mutações encontradas e o fenótipo. Método: Avaliação clínica de 105 pacientes, seguindo um protocolo estabelecido. A identificação de mutações de ponto foi realizada em DNA de sangue periférico por sequenciamento da região codificante do gene amplificada por PCR. Resultados: Em 68% dos pacientes observou-se o quadro clássico da síndrome. Mutações de ponto patogênicas foram encontradas em 64,1% dos pacientes e em 70,42% das pacientes com o quadro clássico. Quatro novas variações de seqüência foram identificadas e sua natureza sugere patogenicidade. Correlações genótipo-fenótipo foram estabelecidas. Conclusão: Descrições clínicas detalhadas desta população brasileira de pacientes acrescenta conhecimento às correlações genótipo-fenótipo nesta grave condição, que podem auxiliar na implantação de programas de triagem de mutações. PALAVRAS-CHAVE: síndrome de Rett, correlações genótipo-fenótipo.