AUTHOR=Mitra Amit K. , Stessman Holly A. F. , Schaefer Robert J. , Wang Wen , Myers Chad L. , Van Ness Brian G. , Beiraghi Soraya 

TITLE=Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate

JOURNAL=Frontiers in Genetics

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00088

DOI=10.3389/fgene.2016.00088

ISSN=1664-8021

ABSTRACT=<p>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 <italic>MYO5B</italic> 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 <italic>MYO5B</italic> SNP rs183559995 GA genotype had an odds ratio of 18.09 (95% Confidence Interval = 1.86–176.34; gender-adjusted <italic>P</italic> = 0.0019) compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (<italic>LOXHD1</italic>), rs6507992 (<italic>SKA1</italic>), rs78950893 (<italic>SMAD7</italic>), rs8097060, rs17713847 (<italic>SCARNA17</italic>), rs6507872 (<italic>CTIF</italic>), rs8091995 (<italic>CTIF</italic>), and rs17715416 (<italic>MYO5B</italic>). 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.</p>