Genome-wide Screen for Neural Tube Defects Reveals Candidate Genes on Chromosomes 7 and 10

Marcy C. Speer, Ph.D.
Duke University Medical Center
P30ES11961 and U19ES11375

Background: Neural tube defects are the second most common severely disabling form of human birth defects in the world. There are three major types of neural tube defects all with devastating consequences. Anencephaly is lethal in all cases; children with encephelocele may survive but are almost always mentally retarded; and children with spina bifida, an open spinal lesion, have varying degrees of muscle weakness and sensory disorders.

Neural tube defects are thought to be caused by a complex interaction between a person's genetic makeup and environmental exposures. Several lines of evidence suggest a genetic component most notably the increased rate of recurrence in siblings and the increased risk of defects in the offspring of a person with a neural tube defect. The most important environmental risk factor for neural tube defect is insufficient folate consumption by the mother around the time of conception. Folate supplementation reduces the risk of neural tube defect recurrence by 50-70%, but it does not entirely eliminate the risk suggesting underlying genetic factors. However, studies of folate and other developmentally related genes in humans have failed to identify a definitive gene causing neural tube defects.

Advance: In a nation-wide collaborative effort conducted in fourteen research facilities across the U.S. and funded by NICHD, NINDS, and NIEHS, new insights have been gained as to the possible sites of a neural tube defect gene or genes. Using 44 families with more than one occurrence of a neural tube defect, researchers have identified two candidate genes on human chromosome 7 and three on chromosome 10. These results will help to prioritize future studies of candidate neural tube disorder genes.

Implications: These researchers plan to add additional families to their analyses as they are identified and become available. They are also contemplating expanding the neural tube disorder classification to increase the sample size and integrating other data such as those from mouse models of neural tube defects. The data in the present study represent an important step in narrowing the search for the gene or genes responsible for neural tube defects and bring the medical community closer to the day when individual predictions of neural tube defect risk may be possible.

Citation: Rampersaud E, Bassuk AG, Enterline DS, George TM, Siegel DG, Melvin EC, Aben J, Allen J, Aylsworth A, Brei T, Bodurtha J, Buran C, Floyd LE, Hammock P, Iskandar B, Ito J, Kessler JA, Lasarsky N, Mack P, Mackey J, McLone D, Meeropol E, Mehltretter L, Mitchell LE, Oakes WJ, Nye JS, Powell C, Sawin K, Stevenson R, Walker M, West SG, Worley G, Gilbert JR, Speer MC. Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10. J Med Genet. 2005 Dec;42(12):940-6.