Nonsyndromic cleft lip with or without cleft palate (CL-P) is a common congenital anomaly with incidence ranging from 1 in 300 to 1 in 2,500 live births. We analyzed two Indian pedigrees (UR017 and UR019) with isolated, nonsyndromic CL-P, in which the anomaly segregates as an autosomal dominant trait. The phenotype was variable, ranging from unilateral to bilateral CL-P. A genomewide linkage scan that used ∼10,000 SNPs was performed. Nonparametric linkage (NPL) analysis identified 11 genomic regions (NPL > 3.5; P < .005) that could potentially harbor CL-P susceptibility variations. Among those, the most significant evidence was for chromosome 13q33.1-34 at marker rs1830756 (NPL = 5.57; P = .00024). This was also supported by parametric linkage; MOD score (LOD scores maximized over genetic model parameters) analysis favored an autosomal dominant model. The maximum LOD score was 4.45, and heterogeneity LOD was 4.45 (α = 100%). Haplotype analysis with informative crossovers enabled the mapping of the CL-P locus to a region of ∼20.17 cM (7.42 Mb) between SNPs rs951095 and rs726455. Thus, we have identified a novel genomic region on 13q33.1-34 that harbors a high-risk variant for CL-P in these Indian families.
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We thank the patients for their cooperation in the study. We are grateful to the pediatric surgeons, plastic surgeons, and dentists, for referring patients. The study was supported in part by Green Cross Blood Bank, Ahmedabad, Gujarat, India. S.K.N. was supported by Oklahoma Medical Research Foundation institutional grant 9124, for linkage analysis.