Analysis of the recurrence patterns for nonsyndromic cleft lip with or without cleft palate in the families of 3,073 Danish probands

Abstract

The identification of several putative susceptibility loci for nonsyndromic cleft lip with or without cleft palate (CL +/- P) has sparked a renewed interest in the genetics of this condition. However, prior to undertaking linkage studies for complex traits such as CL +/- P it is desirable to have some understanding of the number and nature of the loci involved in disease susceptibility. The ability to obtain valid estimates of these parameters is contingent on the availability of family data which are unbiased by factors that distort the true familial recurrence pattern. In an effort to obtain such data, 2 centralized data repositories (the Danish Central Person Registry and the Danish Facial Cleft Database), were linked and used to estimate the risks to first, second, and third-degree relatives of 3,073 CL +/- P probands born in Denmark from 1952 to 1987. Analyses of these data excluded single locus and additive multilocus inheritance of CL +/- P, and provided evidence that CL +/- P is most likely determined by the effects of multiple interacting loci. Under a multiplicative model, no single locus can account for more than a threefold increase in the risk to first-degree relatives of CL +/- P probands. These data provide further evidence that nonparametric linkage methods (ex. affected relative pair studies) are likely to represent a more realistic approach for identifying CL +/- P susceptibility loci, than are traditional pedigree-based methods. However, at least 100 and more realistically several hundred (300-500) affected sib pairs are likely to be required to detect linkage to CL +/- P susceptibility loci.