GWAS reveals loci associated with velopharyngeal dysfunction

• DOI: 10.1038/s41598-018-26880-w
• Publication Date: 2018-05-25T10:50:24Z
• Authors: Jonathan Chernus; Jasmien Roosenboom; Matthew Ford; Myoung Keun Lee; Beth Emanuele; Joel Anderton; Jacqueline T. Hecht; Carmencita Padilla; Frederic W. B. De...; Carmen J. Buxo; Eleanor Feingold; Elizabeth J. Leslie; John R. Shaffer; Seth M. Weinberg; Mary L. Marazita
• Keywords: Adult; Male; Cancer Research; Genome-wide association study; Velopharyngeal Insufficiency; Adolescent; Etiology; Genotype; Velopharyngeal insufficiency; Role of Long Noncoding RNAs in Cancer and Development; Polymorphism, Single Nucleotide; Gene; Article; Linkage Disequilibrium; Proband; Young Adult; Craniofacial; 03 medical and health sciences; Antigens, CD; Genetics and Development of Craniofacial Abnormalities; Biochemistry, Genetics and Molecular Biology; Receptors, Transferrin; Genetics; Humans; Choline-Phosphate Cytidylyltransferase; Child; Biology; Internal medicine; Single-nucleotide polymorphism; 0303 health sciences; Life Sciences; Positional Plagiocephaly; Audiology; Middle Aged; DNA-Binding Proteins; Cleft Palate; Phenotype; Genetic Loci; Genetic and Environmental Influences on Cleft Lip and Palate; FOS: Biological sciences; Subclinical infection; Mutation; Medicine; Pharyngeal flap; Female; Anatomy; Genome-Wide Association Study

AbstractVelopharyngeal dysfunction (VPD) occurs when the muscular soft palate (velum) and lateral pharyngeal walls are physically unable to separate the oral and nasal cavities during speech production leading to hypernasality and abnormal speech reduction. Because VPD is often associated with overt or submucous cleft palate, it could be present as a subclinical phenotype in families with a history of orofacial clefting. A key assumption to this model is that the overt and subclinical manifestations of the orofacial cleft phenotype exist on a continuum and therefore share common etiological factors. We performed a genome-wide association study in 976 unaffected relatives of isolated CP probands, 54 of whom had VPD. Five loci were significantly (p < 5 × 10−8) associated with VPD: 3q29, 9p21.1, 12q21.31, 16p12.3 and 16p13.3. An additional 15 loci showing suggestive evidence of association with VPD were observed. Several genes known to be involved in orofacial clefting and craniofacial development are located in these regions, such as TFRC, PCYT1A, BNC2 and FREM1. Although further research is necessary, this could be an indication for a potential shared genetic architecture between VPD and cleft palate, and supporting the hypothesis that VPD is a subclinical phenotype of orofacial clefting.