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Polymorphisms increase risk for Down syndrome
  
By Bijal P. Trivedi

Though the incidence of Down syndrome is about one in 700 births and is the most common cause of mental retardation, little is known about what factors, other than age, increase a woman's risk of bearing children with the disease.

Now Arkansas researchers in Little Rock have found polymorphisms in two genes that could increase a mother's chance of having children with this birth defect. These results are published in the September issue of The American Journal of Human Genetics.

The genes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are involved in metabolizing the essential vitamins folate and B12. Both genes, if mutated, interfere with the essential processes of DNA synthesis and DNA methylation.

The team studied MTHFR and MTRR in 157 mothers whose babies had Down syndrome and in 144 mothers whose babies were not affected. The research shows that when nucleotide 677 of the MTHFR gene is changed from cytosine to thymine, the chance of having a child with Down syndrome almost doubles. A polymorphism in the MTRR gene that changes nucleotide 66 from adenine to guanine increases the risk of a Down syndrome baby by two and a half fold. A mother who carries both polymorphisms is likely to have a four-fold increase in risk.

Down syndrome is a birth defect that results from getting three copies, rather than the normal two, of chromosome 21. The risk of producing the extra chromosome is increased in older mothers.

The researchers suggest that normal DNA synthesis and methylation are essential for chromosome separation during the process of egg formation. The authors also point out that an inadequate supply of folate or B12 in the diet could amplify the genetic effects of the MTHFR and MTRR polymorphisms.

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Hobbs, C.A. et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 67, 623-630 (September 2000).
 

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