1. Departments of Medical Genetics and Medicine, School of Medicine, Indiana University, Indianapolis, Indiana 46202.

Abstract

ANENCEPHALY, spina bifida and related midline neurological defects are among the commonest severe congenital malformations in man for which a specific aetiology is still unknown. The deformities frequently occur together or in close relatives and, although their prevalence rates vary widely in different populations¹ and have shown impressive secular trends within populations², the rates are highly correlated, a fact which suggests a common aetiology. There is a well established recurrence risk of 4–5 per cent following the birth of the first affected child in a sibship, and for this reason a genetic aetiology has long been considered likely. No evidence for increased parental consanguinity has been found, and polygenic inheritance has in the past usually been accepted as the most satisfactory explanation for the known facts³. In 1968, however, Yen and MacMahon concluded that the recurrence risk for anencephaly and spina bificla could not be genetically determined because in none of 105 twin pairs taken from their own studies and other consecutive series in the literature was concordance for either deformity observed⁴. Furthermore, these authors noted that the recurrence risk for maternal half-siblings appeared to be as great as that for full siblings, an observation which they felt was inconsistent with genetic determination. As an alternative hypothesis, Yen and MacMahon suggested that the recurrence risk, variation in population frequencies and observed secular trends may all be attributable to an unidentified environmental factor. The twin data are, however, as difficult to reconcile with environmental causation as they are with either monogenic or polygenic Mendelian inheritance, because individual variation in the observed response to external teratogenie influences, be they environmental or maternal, must also arise, at least in part, from genetic differences in exposed foetuses. In either case, a high concordance rate might be expected among identical twins.