Vintiner, Gillian Mary; (1993) Mapping of genes involved in cleft lip with or without cleft palate. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Candidate genes for CL/P were selected on the basis of involvement in cytogenetic alterations, from published linkage and association studies, and from regions linked to syndromes within which clefting occurs. Linkage analyses were carried out with 8 families with an apparent autosomal dominant inheritance of non-syndromic CL/P, while the association analyses involved 57 unrelated British Caucasian individuals with CL/P and 60 controls. Linkage was excluded between markers D1S65 and D1S58 (lq31), thought to flank the Van der Woude syndrome locus, and the families with CL/P. Multipoint analysis excluded linkage between CL/P and the 2 loci with a maximum lod score of z=-4.0. An association between an RFLP at TGFA (2p13) was confirmed (X2=15.04, p<0.001) although there was no evidence of linkage between TGFA and familial CL/P (z=-3.152, Θ=0.05). CRTL1 (5q15) was also excluded from a role in the formation of familial CL/P (z=-3.466, Θ=0.05). Amplification of this locus in a 5q- hybrid of an individual with syndromic CP, mapped the translocation breakpoint below 5ql5. Contrary to a published report there was no linkage between F13A1 (6p24) and CL/P (z=-2.052, Θ=0.05). There was no association between VIM (10p13) and the unrelated clefted individuals (X2=0.110, p>0.5). FISH analysis using two cosmids identified by VIM in a cosmid library screen, did not reveal if VIM was involved in a 10p13 translocation breakpoint in an individual with CL/P. There was no association between KARA (17q21) and unrelated clefted individuals (X2=0.954, p>0.1). Linkage also excluded RARA from a role in familial clefting (z=-3.211, Θ=0.001). In addition to this work, a linkage analysis was carried out between COL2A1 and 6 families with an autosomal dominant inheritance of Stickler syndrome. A maximum lod score of z=0.96, Θ=0.100 was suggestive of either genetic heterogeneity or the involvement of a locus closely linked to COL2A1.

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