Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population.

Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR-RFLP, and found significant differences for both BHMT 742G>A genotype (P=0.04) and allele (P=0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG=0.45; GA=0.45 and AA=0.10 in CM, and GG=0.54; GA=0.38 and AA=0.02 in DSM. Allelic frequencies were G=0.68 and A=0.32 in CM and G=0.78 and A=0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40% the risk of bearing a DS child (OR=0.61; 95% CI: 0.40-0.93; P=0.03), and the risk is diminished up to >80% in association with the homozygous genotype (OR=0.17; 95% CI: 0.04-0.80; P=0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington's disease.

We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington's disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter- and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r=-0.84; P<0.001) and no correlation between the number of CCG repeats and the age of disease onset (r=0.06). We found 40 different haplotypes and the analysis showed that (CCG)(10) was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG)(7) was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG)(10) was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG)(7) was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG)(7) with the expanded CAG alleles (χ(2)=6.97, P=0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG)(7) is the most frequent allele, similarly to our findings.