PREDICTION OF LIABILITY TO OROFACIAL CLEFTING USING GENETIC AND CRANIOFACIAL DATA FROM PARENTS

Background-Cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) are separate clinical entities and for both polygen ic multifactorial aetiology has been proposed. Parents of children wit h orofacial clefting have been shown to have distinctive differences i n their facial shape when compared to matched controls. Objective-To t est the hypothesis that genetic and morphometric factors predispose to orofacial clefting and that these markers differ for CL(P) and CP. Me thods-Polymorphisms at the transforming growth factor alpha (TGF alpha ) locus in 83 parents of children with nonsyndromic orofacial clefts w ere analysed, and their craniofacial morphology was assessed using lat eral cephalometry. Results-Parents of children with CL(P) and CP showe d an increased frequency of the TGF alpha/TaqI C2 allele (RR=4.10, p=0 .009) relative to the comparison group. Also the TGF alpha/BamHI A1 al lele was more prevalent in the CP parents. Multivariate statistical an alysis-Using stepwise logistic regression analysis the TGF alpha/Taq1 C2 polymorphism provides the best model for liability to orofacial cle fting. To determine the type of clefting a model involving interaction between the parental TGF alpha/BamHI and TGF alpha/RsaI genotypes sho wed the best fit. Using genotype only to predict the clefting defect i n the children according to parental genotype, 68.3% could be correctl y classified. By adding information on craniofacial measurements in th e parents, 76% of CP and 94% of CL(P) parents could be correctly class ified. Conclusions-This study provides a model for prediction of liabi lity to orofacial clefting, These findings suggest that different mole cular aberrations at the TGF alpha locus may modify the risk for CP an d CL(P).