Genetic Factors in Birth Defects

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Approximately 20 major malformations have been identified for future investigations. Cases with the major birth defects of interest have been selected from the Congenital Malformations Registry along with suitable control subjects. Data from the Registry have been linked with the state's Newborn Screening Program to identify filter paper samples for DNA extraction. Samples have been selected and DNA has been extracted for many projects. The first reports have been completed and have been submitted for publication. Two are currently under review. In addition genotyping is now complete for three other projects, congenital diaphragmatic hernia, limb defects, and fetal alcohol syndrome. Analysis of these data is underway. Samples for other projects are being identified, undergoing DNA extraction, or being genotyped for single nucleotide polymorphisms (SNPs. The first completed projects are on omphalocele and Hirschsprung's disease. The omphalocele investigation found an association between being a case and the transcobalamin 2 (vitamin B12) receptor gene. If confirmed, this finding suggests that B12 may be useful in preventing omphaloceles and may also explain previous work that showed an association between maternal multivitamin use and reduced risk for omphalocele. This study also found a suggestive association between other genes related to homocysteine metabolism and omphalocele. These findings suggest that homocysteine metabolism (which is related to vitamin B12) could be causally related to omphalocele. The second completed project examined genes related to migration of neural tissue and Hirschsprung's disease. New variants of a gene previously reported to be related to Hirschsprung's disease,RET, were found by sequencing. Other potentially important genes involved in migration were also found. Work is continuing to identify cases and obtain samples from the bank for DNA extraction. Data are also being reviewed to identify rare defects for study by a different approach. DNA will be analyzed by large scale arrays to identify copy number variants.