Lees, Melissa M.; (1998) Complex genetics of nonsyndromic cleft lip and palate. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a genetically complex disorder. It is the most common craniofacial malformation, with an incidence of between 1 in 700 and 1 in 1000 in Caucasian populations. Although CL/P appears to have a significant genetic component (with a s of at least 30), finding contributing genes by classic linkage analysis has proved difficult, probably due to the complexity of the disorder. This thesis considers the evidence of CL/P as a complex disease. Genetic analysis of CL/P using nonparametric methods, found to be successful with other complex diseases, was performed on a large cohort of familial cases from throughout the UK. Initially a number of candidate genes were examined for linkage and association to CL/P, A genome-wide scan was then commenced, genotyping 356 individuals from 92 affected sib-pair (ASP) families. The thesis includes the results from the 11 chromosomes analysed to date, using Genehunter and Mapmaker/Sibs, based on allele sharing methods, and the Transmission Disequilibrium test. This study has identified, from the 11 chromosomes analysed, 7 new regions (1p36, 1q24, 1q42, 2q37, 6q25, 18p11 and 21q22) which may be implicated in the pathogenesis of CL/P, and confirms the involvement of a further 2 loci previously identified by candidate gene analysis (6p23 and TGFA on 2p13), adding evidence to their consideration as susceptibility loci. These results are awaiting replication to confirm their contribution. Linkage analysis of families with the Popliteal Pterygium syndrome, a syndromic cause of clefting, for markers on 1q32 at the Van der Woude locus, was consistent with the hypothesis that these disorders are allelic due to different mutations within the same gene. By identifying susceptibility genes, light will be shed on the disease pathogenesis, and progress may be made towards identifying any preventable etiologic factors.

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