Abstract
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P. In the current study, we performed exome sequencing on 12 familial genomes (six affected individuals, two obligate carriers, and four seemingly unaffected individuals) of a six-generation family to identify candidate SNPs associated with NSCL/P risk. Subsequently, targeted bidirectional DNA re-sequencing of polymerase chain reaction (PCR)-amplified high-risk regions of MYO5B gene and sequenom iPLEX genotpying of 29 candidate SNPs were performed on a larger set of 33 members of this NSCL/P family (10 affected + 4 obligate carriers + 19 unaffected relatives) to find SNPs significantly associated with NSCL/P trait. SNP vs. NSCL/P association analysis showed the MYO5B SNP rs183559995 GA genotype had an odds ratio of 18.09 (95% Confidence Interval = 1.86–176.34; gender-adjusted P = 0.0019) compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). We could thus identify mutations in several genes as key candidate SNPs associated with the risk of NSCL/P in this large multi-generation family.
Highlights
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital craniofacial birth defects that accounts for 93–95% cases of Cleft Lip with or without Cleft Palate (CL/P) and represents almost half of facial dysmorphology (Stuppia et al, 2011)
Mutations in several genes have been shown associated with increased risk of NSCL/P in recent years including a causative variant in the promoter region of IRF6 gene (Rahimov et al, 2012; Leslie et al, 2015)
Our results identified single nucleotide polymorphism (SNP) within several genes in the 18q21.1 region as potentially pathogenic variants associated with high risk of NSCL/P in this family
Summary
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital craniofacial birth defects that accounts for 93–95% cases of Cleft Lip with or without Cleft Palate (CL/P) and represents almost half of facial dysmorphology (Stuppia et al, 2011). NSCL/P consists of isolated, nonspecific malformations of the upper lip and oral cavity and is seen frequently worldwide with average global incidence of 1.7 per 1000 live births and 1 per 700–1000 newborns in the United States each year. Mutations in several genes have been shown associated with increased risk of NSCL/P in recent years including a causative variant in the promoter region of IRF6 gene (chromosome 1q32.2) (Rahimov et al, 2012; Leslie et al, 2015). Genome-wide linkage analysis and genome-wide association studies (GWAS) have identified and validated association of 13 different genetic loci with the risk of NSCL/P (Leslie et al, 2015). The evidences have been largely conflicting and the causal pathogenic variants underlying NSCL/P risk still remains unknown
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