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Pathogenic variants in EDNRA signaling pathway components EDNRA<\/jats:italic>, GNAI3<\/jats:italic>, PCLB4<\/jats:italic>, and EDN1<\/jats:italic> cause Mandibulofacial Dysostosis with Alopecia (MFDA), Auriculocondylar syndrome (ARCND) 1, 2, and 3, respectively. However, cardiovascular development is normal in MFDA and ARCND individuals, unlike Ednra<\/jats:italic> knockout mice. One explanation may be that partial EDNRA signaling remains in MFDA and ARCND, as mice with reduced, but not absent, EDNRA signaling also lack a cardiovascular phenotype. Here we report an individual with craniofacial and cardiovascular malformations mimicking the Ednra<\/jats:italic>\n\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse phenotype, including a distinctive micrognathia with microstomia and a hypoplastic aortic arch. Exome sequencing found a novel homozygous missense variant in EDNRA<\/jats:italic> (c.1142A>C; p.Q381P). Bioluminescence resonance energy transfer assays revealed that this amino acid substitution in helix 8 of EDNRA prevents recruitment of G proteins to the receptor, abrogating subsequent receptor activation by its ligand, Endothelin\u20101. This homozygous variant is thus the first reported loss\u2010of\u2010function EDNRA<\/jats:italic> allele, resulting in a syndrome we have named Oro\u2010Oto\u2010Cardiac Syndrome. Further, our results illustrate that EDNRA signaling is required for both normal human craniofacial and cardiovascular development, and that limited EDNRA signaling is likely retained in ARCND and MFDA individuals. This work illustrates a straightforward approach to identifying the functional consequence of novel genetic variants in signaling molecules associated with malformation syndromes.<\/jats:p>","DOI":"10.1002\/ajmg.a.61531","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T09:53:02Z","timestamp":1583401982000},"page":"1104-1116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Loss\u2010of\u2010function of Endothelin receptor type A results in Oro\u2010Oto\u2010Cardiac syndrome"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-8985","authenticated-orcid":false,"given":"Amanda Barone","family":"Pritchard","sequence":"first","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-0624","authenticated-orcid":false,"given":"Stanley M.","family":"Kanai","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Krock","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Schindewolf","sequence":"additional","affiliation":[{"name":"Center for Fetal Diagnosis and Treatment, Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Oliver\u2010Krasinski","sequence":"additional","affiliation":[{"name":"Department of Pathology The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla","family":"Khalek","sequence":"additional","affiliation":[{"name":"Center for Fetal Diagnosis and Treatment, Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najeah","family":"Okashah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Medical College of Georgia\u2010Augusta University Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin A.","family":"Lambert","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Medical College of Georgia\u2010Augusta University Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre L.P.","family":"Tavares","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Zackai","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2008-477X","authenticated-orcid":false,"given":"David E.","family":"Clouthier","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology University of Colorado Anschutz Medical Campus Aurora Colorado 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