Genetic analysis in families with van der Woude syndrome.

We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS). Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K = .89 and .99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP. On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likely to transmit VWS. However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity. The expression of VWS is significantly modified by the genetic background: More extreme phenotypes in parents tend to produce more extreme expression in their children. For a VWS gene carrier the relative risk of transmitting a cleft is 26.45%; that of transmitting lower lip pits is 23.55%. Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the three target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1.8 X 10(-5).