GENETIC-ANALYSIS IN FAMILIES WITH VANDERWOUDE SYNDROME

Abstract

Information was brought together on 864 affected individuals in 164 famiies (including 3 new pedigrees) reported in the 137 yr period since 1845 when Demarquay first described a family with what was later claled van der Woude syndrome (VWS ). Both types or ofral 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 autoosmal dominant mode with high penetrance estimated to be K = 0.89 and 0.99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, i.e., about about twice as many clefted individuals have CLP as have CP. The usually observed excess of females wit CP and excess of males with CLP was not found, in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likey to transmit VWS. 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 diferential 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 riskof transmitting a cleft is 26.45%; that of transmitting lower lip pits is 23.55%. Three pedigree of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the 3 target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1.8 .times. 10-5.