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NSCL\/P is a multifactorial disorder with genetic and environmental factors playing etiologic roles. Currently, only 25% of the genetic variation underlying NSCL\/P has been identified by linkage, candidate gene and genome-wide association studies. In this study, whole-genome sequencing and genome-wide genotyping followed by polygenic risk score (PRS) and linkage analyses were used to identify the genetic etiology of NSCL\/P in a large three-generation family. We identified a rare missense variant in PDGFRA (c.C2740T; p.R914W) as potentially etiologic in a gene-based association test using pVAAST (P\u2009=\u20091.78\u00a0\u00d7\u00a010\u22124) and showed decreased penetrance. PRS analysis suggested that variant penetrance was likely modified by common NSCL\/P risk variants, with lower scores found among unaffected carriers. Linkage analysis provided additional support for PRS-modified penetrance, with a 7.4-fold increase in likelihood after conditioning on PRS. Functional characterization experiments showed that the putatively causal variant was null for signaling activity in vitro; further, perturbation of pdgfra in zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rare PDGFRA variant, modified by additional common NSCL\/P risk variants, have a profound effect on NSCL\/P risk. These data provide compelling evidence for multifactorial inheritance long postulated to underlie NSCL\/P and may explain some unusual familial patterns.<\/jats:p>","DOI":"10.1093\/hmg\/ddac037","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T04:15:04Z","timestamp":1644380104000},"page":"2348-2357","source":"Crossref","is-referenced-by-count":24,"title":["Polygenic risk impacts<i>PDGFRA<\/i>mutation penetrance in non-syndromic cleft lip and palate"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2727-1746","authenticated-orcid":false,"given":"Yao","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Epidemiology , University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Center for RNA Therapeutics , Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Department of Cardiovascular Sciences , Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E","family":"Petty","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute , Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J","family":"Bohlender","sequence":"additional","affiliation":[{"name":"Department of Epidemiology , University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M","family":"Shaw","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute , Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E","family":"Below","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute , Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada","family":"Bejar","sequence":"additional","affiliation":[{"name":"Center for RNA Therapeutics , Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Department of Cardiovascular Sciences , Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar E","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavna","family":"Tandon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Pediatric Research Center , UTHealth McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George T","family":"Eisenhoffer","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L","family":"Kiss","sequence":"additional","affiliation":[{"name":"Center for RNA Therapeutics , Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA"},{"name":"Department of Cardiovascular Sciences , Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad D","family":"Huff","sequence":"additional","affiliation":[{"name":"Department of Epidemiology , University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadne","family":"Letra","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences , UTHealth School of Dentistry at Houston, Houston, TX 77054, USA"},{"name":"Center for Craniofacial Research , UTHealth School of Dentistry at Houston, Houston 77054, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T","family":"Hecht","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Pediatric Research Center , UTHealth McGovern Medical School, Houston, TX 77030, USA"},{"name":"Center for Craniofacial Research , UTHealth School of Dentistry at Houston, Houston 77054, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"2022072316290706300_ref1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. 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