Genome‐scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey

Abstract

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.

Progress toward discerning the genetics of cleft lip

“…Recently, mutations in MSX1 have been identified in 2% of patients with nonsyndromic orofacial clefting [22,23•]. These data support previous associations of MSX1 with orofacial clefting [9, [24][25][26][27][28].…”

“…The first CL/P scan was performed on 92 British sibpairs and identified a total of nine regions with suggestive results [49]. This has been followed by five additional scans of varying size (Table 2) [20,24,[49][50][51][52][53][54]. In general, the results have been modest with the exception of a log odds ratio (LOD) score of 3.0 at 17p13.1 in a scan of two large Syrian families [50].…”

CRISPLD2: a novel NSCLP candidate gene

“…This region was first identified by Prescott et al in a genome scan of Caucasian NSCLP sib pairs, and subsequently in four other genome scans of different NSCLP populations (19,21,25,26,28). Analysis of STR D16S3037 in our dataset provided evidence for an association with NSCLP (P = 0.00063).…”

“…Egfr, Bmp4, Bmpr1 and Folbp1) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Eight genome scans have identified regions that may potentially harbor NSCLP susceptibility genes (19)(20)(21)(22)(23)(24)(25). In 2000, Prescott et al (26) identified nine chromosomal regions that are associated with orofacial clefting in their Caucasian NSCLP sib-pair population.…”

“…Linkage disequilibrium (LD) analysis identified STR marker D16S3037, in the 16q24.1 chromosomal region, that was significantly associated with NSCLP (P = 0.00063). Results from three other NSCLP genome scans and one targeted genome scan have also suggested that a NSCLP candidate gene lies on the long arm of chromosome 16, between 16q21-24, which includes D16S3037 (19,21,25,28).…”