DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000. A number of genetic loci have shown positive linkage or association results in European Caucasian populations. The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci. Eighteen affected individuals with consanguineous parents were identified as part of our on-going studies of orofacial clefts in Ankara, Turkey. Genotyped were 383 genome-scan markers, and 70 additional markers, including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 (TGFA, D4S175, F13A1, TGFB3, D17S250, and APOC2) that have been implicated in other studies of families with orofacial clefting. LOD scores (two point and multiple point) and family-based association statistics (TDT) were calculated between each of the markers and CL/P. For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P. Of the six candidate markers, significant TDT results were obtained with TGFA (P = 0.05). The most statistically significant multipoint results from the linkage genome scan were between putative genes controlling risk of CL/P and regions on chromosomes 4, 10, 12, and 15 (maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively). These results demonstrate the power of small numbers of families with inbred probands to detect linkage and association.

In order to identify genes or regions involved in nonsyndromic cleft lip with or without cleft palate (CL/P) in families from India, we analyzed 38 multiplex families (DNA from 272 individuals, 82 affected with CL/P, 190 unaffected) for 285 genome-wide markers (average spacing 12.6 cM), including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 that have been implicated in other studies of CL/P. LOD scores (two-point and multipoint), and model-free association (TDT) and linkage (NPL) statistics, were calculated between each of the markers and a hypothetical CL/P susceptibility locus. The most statistically significant two-point linkage results were with markers on chromosome 7 (LOD = 1.89 with D7S435, 7p15, 47 cM), chromosome 5 (LOD = 1.76 with D5S407, 5q11, 65 cM), chromosome 15 (LOD = 1.55 with D15S652, 15q26, 90 cM), and chromosome 20 (LOD = 1.46 with STS155130, 20q13, 54 cM). The most significant multipoint linkage result was on chromosome 5q, again near D5S407 (HLOD = 1.40). Regions on chromosomes 1p, 1q, 7q, 12q, 16q, 18q, and Xp also had a LOD or HLOD > or = 1.0. Of seven candidate markers and regions with previous positive reports in the literature (TGFA, MSX1, D4S175, F13A1, TGFB3, D17S250, and APOC2), none had a significant linkage result, but one (the APOC2 region) had a significant association result and three others (TGFA, MSX1, F13A1) had suggestive results. The results are consistent with the involvement of multiple loci in CL/P expression in this West Bengal population, which concurs with results found in other CL/P study populations.

Objective-Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome.Results-Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08).Conclusion-Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate.An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.