Genome‐wide linkage scan of nonsyndromic orofacial clefting in 91 families of central European origin

Abstract

Orofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome-wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome-wide linkage analyses, we searched for sex-specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21-q26 and 1p31-p21, with the chromosome 1 locus showing a male-specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC-associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex-specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO.

Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers

“…A prototypical example is the gene desert at human chromosome 8q24. A 640kb region in this interval is devoid of protein-coding genes, but is a major susceptibility locus for cleft palate with a calculated population attributable risk of 41% (35, 52, 53) and is significantly linked to normal variation in several facial morphology traits (16). We identified four craniofacial enhancer candidate sequences in this risk interval, two of which drive reproducible craniofacial reporter activity at e11.5 in transgenic mice (fig.…”

Strong Association of Variants aroundFOXE1and Orofacial Clefting

“…Recruitment of cases in the Bonn sample is described in detail elsewhere (Mangold et al, 2009). The Bonn sample comprised 623 nsCL/P cases (392 male, 231 female) and 100 nsCPO cases (37 male, 63 female).…”

Human Stem Cell Cultures from Cleft Lip/Palate Patients Show Enrichment of Transcripts Involved in Extracellular Matrix Modeling By Comparison to Controls

“…Although gene mapping approaches, such as Genome-Wide Association Studies (GWAS), appeared to offer an option to identify at-risk alleles associated with NSCL/P, with better reproducibility among different studies [10, 11, 17, 18] than candidate genes, lack of progress over the last decade suggests that GWAS are still unlikely to provide sufficient information on the genetic etiology underlying the disease. However, genome-wide expression analyses based on differential gene expression associated with NSCL/P, as proposed here; present a viable and challenging alternative, since patterns of co-expression can be used to identify biological pathways or gene networks associated with disease predisposition.…”