Prescott, Natalie Joy; (2000) An investigation of the genetic etiology of nonsyndromic cleft lip with or without cleft palate. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex disorder of multigenic origin involving between 2 and 10 loci. Linkage and association studies of CL/P have implicated a number of candidate genes and regions, but have often proved difficult to replicate. This thesis reports the findings from a two stage, genome-wide scan of 92 CL/P affected sibling pedigrees. Excessive allele sharing was observed on 8 chromosomes at the regions of 1p36, 2p13, 5q34-qter 6p24-23, 6q25, 8q23-24, 11cen, 13q12-22, 16q22-24, 18ptel-q11.3, 21ptel-q11 and Xcen-q. Two of these (the TGFA locus on 2p13, and 6p24-23) have previously been implicated in CL/P by association and linkage studies. A third area at 1p36, which harbours the MTHFR gene encoding an enzyme involved in folate metabolism, is a candidate because of previous evidence implicating maternal folate deficiency in oral clefting. This study also demonstrated highly suggestive linkage to a novel susceptibility locus for nonsyndromic clefting on the X chromosome. In the light of these findings a candidate gene evaluation was performed on 223 CL/P trios, to examine polymorphic variants of TGFA(2p13), Endothelin1(6p24- 23), and MTHFR(1p36) by transmission disequilibrium testing (T/DT). A significant association between a variant allele of MTHFR and CL/P was demonstrated. This variant does not reduce MTHFR enzyme activity and is most likely reflecting a region of linkage disequilibrium around a clefting susceptibility locus. In addition a significant association between the common TGFA C1 allele and CL/P was observed. Previous associations at this locus have been with the alternate rare C2 allele, thus these findings discount the possibility that this rare allele represents a cleft mutation. No evidence of linkage disequilibrium could be detected at the 6p24 locus. In conclusion, analysis of IBD sharing in affected siblings has confirmed the existence of a CL/P susceptibility locus at 6p24-23, and added further evidence through linkage and association for a locus at 2p13 although this locus may not necessarily involved the TGFA gene. In addition, 10 novel loci, that may be involved in clefting etiology have been identified. None reached genome-wide significance, however, linkage and linkage disequilibrium data suggest tentative assignment of CL/P loci to Xq21 and 1p36.3.

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