Timothy George, M.D.
Richard H Finnell, Ph.D.
Bermans Iskandar, M.D.
Graham Fieggen, M.D.
Rick Abbott, M.D.
Evidence of a genetic factor is strengthened by the presence of a family history in a number of members having neural tube defects. While a family history of neural tube defects has been reported in up to 8.5% of families bearing a child with a neural tube defect,, further inspection of these families shows that affected parent-child pairs are rare; most affected relative pairs are related at either the second or third degree, thus suggesting oligogenic inheritance (14). More data on parent-child transmission will be available over the next two decades, as children born with neural tube defects now receive sufficiently sophisticated medical care that they can live to maturity and reproduce. Second, neural tube defects have been associated with known genetic syndromes including Meckel syndrome, anterior sacral myelomeningocele with anal stenosis, and the Mohr syndrome. Neural tube defects are frequently associated with trisomies 13 and 18 and various chromosome rearrangements. Third, in neural tube defects occurring without other syndromes, the recurrence risk for siblings is approximately 2–5%, which represents up to a 50-fold increase over the occurrence rate in the general population. Khoury et al. have shown that for a recurrence risk to be this high, an environmental teratogen would have to increase the risk at least 100 fold to exhibit the same degree of familial aggregation, making a genetic component essentially required (13). Such potent teratogens are extraordinarily rare; however, one example of a teratogen exerting such a high relative risk is thalidomide.
Other genetic analyses such as segregation analysis studies have not clearly demonstrated evidence of a major gene due to the admittedly small sample sizes and problems of ascertainment. Twin studies for neural tube defects have been anecdotal in nature, typically comparing concordance in like-sex vs. unlike-sex twins instead of the more formal comparison between dizygotic and monozygotic twins. Chromosome abnormalities, specifically aneuploidy, have been found in 5–17% of patients with neural tube defects. Other chromosomal evidence is furthered by neural tube defects associated with trisomies 13 and 18, and 13q deletion syndromes. These cytogenetic rearrangements can be key positional clues to candidate genes and have been recently summarized (14).
One of the longest running controversies, as yet undecided, is whether neural tube defects at different levels represent different defects. In other words, are rostral level defects (e.g., anencephaly) different in some fundamental way from caudal defects (e.g., myelomeningocele)? Additionally, are lesions that include both rostral and caudal levels (e.g., cranioraschisis) altogether variant embryopathies? If the etiologies of upper and lower lesions are different, then it would be expected that recurrences in families would breed true: affected individuals in an upper lesion family would all have upper lesions and vice versa for lower lesions. Neural tube defects tend to breed true within families; in other words, recurrences in families in which the reference case is affected with spina bifida tend to be spina bifida, and recurrences in families in which the reference case is anencephaly tend to be anencephaly. However, 30–40% of recurrences involve a neural tube defect phenotype that is different from the reference case phenotype. This intra-family heterogeneity may represent the pleiotropic effect of a common underlying gene or may suggest that families with different phenotypic presentations may result from different underlying genes. Alternatively, these dramatic phenotypic differences within families may suggest slight differences in timing to key environmental exposures in susceptible pregnancies or may suggest that the underlying genes are different. Or, these differences may represent the variable outcomes following different environmental exposures at key developmental times or even just the result of random chance. While studies to date have provided conflicting and inconclusive results, the availability of such families will be vital to understanding the genetic and environmental influences on neural tube defects.