Orofacial Cleft 12

<p>For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic CL/P, see 119530.p> Mapping <p>Birnbaum et al. (2009) conducted a genomewide association study involving 224 unrelated patients of Central European origin with nonsyndromic cleft lip with or without cleft palate (NSCL/P) and identified a 640-kb region on chromosome 8q24.21 containing 3 markers that reached genomewide significance. Fine mapping of the 640-kb region in 462 unrelated NSCL/P cases revealed a SNP (rs987525) that was significantly associated with the disorder (p = 3.34 x 10(-24); odds ratio, 2.57 for heterozygotes and 6.05 for homozygotes). The calculated population attributable risk for this marker was 0.41, suggesting that this represents a major susceptibility locus for NSCL/P. p><p>In independent Estonian and Lithuanian samples, Nikopensius et al. (2009) replicated the previously reported association between rs987525 and nonsyndromic oral clefting, obtaining highly significant results in both groups (p = 5.97 x 10(-5) and p = 1.6 x 10(-5), respectively). The odds ratios were 1.58 and 1.89, respectively, for the heterozygous genotype, and 5.56 and 11.13, respectively, for the homozygous genotype. The risk allele frequency in Estonians and Lithuanians, approximately 16%, was lower than the approximately 20% frequency found in the previously reported German control sample (Birnbaum et al., 2009). p><p>Ludwig et al. (2012) conducted the first metaanalyses for NSCL/P using data from the 2 largest genomewide association studies published to that time. The highest risk was associated with the A allele of SNP rs987525 on chromosome 8q24 at genomic position 129.77-130.30 (metaanalysis p value = 5.12 x 10(-35)). The heterozygous relative risk was 1.919 (95% CI, 1.660-2.218); the relative risk for the homozygous state was 4.384 (95% CI, 3.393-5.666). p> Cytogenetics <p>Alkuraya et al. (2006) reported a 5-year-old girl with unilateral nonsyndromic cleft lip and palate who had a balanced translocation between chromosomes 2q33.1 and 8q24.3. At the 2q breakpoint the SUMO1 gene (601912) was interrupted; Alkuraya et al. (2006) suggested that SUMO1 haploinsufficiency leads to CL/P (see OFC10, 601912). p>