Orofacial Cleft 3

<p>For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic cleft lip/palate (CL/P), see 119530.p> Mapping <p>Stein et al. (1995) tested linkage of 22 candidate genes to CL/P in 11 multigenerational families, and excluded 21 of these candidates. APOC2 (608083), which is located at 19q13.1 (or 19q13.2) and which is linked to the protooncogene BCL3 (109560), gave suggestive evidence for linkage to CL/P. The study was expanded to include a total of 39 multigenerational CL/P families. Linkage was tested in all the families, using an anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was tested under 2 models, autosomal dominant with reduced penetrance and affecteds only. Homogeneity testing on the 2-point data gave evidence of heterogeneity at APOC2 under the affecteds-only model. Both models showed evidence of heterogeneity, with 43% of families linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint lod score of 7.00 at BCL3 was found among the 17 families that had posterior probabilities greater than 50% in favor of linkage. The transmission disequilibrium test provided additional evidence for linkage with 3 alleles of BCL3 more often transmitted to affected children. The results were interpreted as suggesting that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families. p><p>Amos et al. (1996) provided data supporting linkage and association between chromosome 19 markers in the vicinity of BCL3 and orofacial cleft. p><p>Wyszynski et al. (1997) pursued the question raised by the suggestion that BCL3 on 19q, or a nearby gene, may play a role in the etiology of nonsyndromic CL/P in some families. They tested 30 U.S. and 11 Mexican multiplex families for 4 markers on 19q. While likelihood-based linkage analysis failed to show significant evidence of linkage, the transmission disequilibrium test indicated highly significant deviation from independent assortment of allele 3 at the BCL3 marker in both datasets and for allele 13 of the D19S178 marker in the Mexican dataset. These results supported an association, possibly due to linkage disequilibrium, between chromosome 19 markers and a putative CL/P locus. p><p>Warrington et al. (2006) searched for an association between orofacial clefts and mutations in the PVR (173850) and PVRL2 (600798) genes, both of which are located on 19q, in 5 different populations. An allelic variant in the PVR gene showed statistically significant association in the South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including 2 rare amino acid changes, 1 in each gene, which were not seen in controls. Warrington et al. (2006) concluded that it was unclear if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation. p>