{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:38:55Z","timestamp":1777523935208,"version":"3.51.4"},"reference-count":81,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Iowa Institute for Oral Health Research"},{"name":"College of Dentistry Student Research Program"},{"name":"Dewel Endowed funds University of Iowa Department of Orthodontics"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["The Cleft Palate Craniofacial Journal"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Oculoauriculovertebral spectrum (OAVS) encompasses abnormalities on derivatives from the first and second pharyngeal arches including macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular, and vertebral anomalies. We present genetic findings on a 3-generation family affected with macrostomia, preauricular tags and ptosis following an autosomal dominant pattern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>We generated whole-genome sequencing data for the proband, affected father, and unaffected paternal grandmother followed by Sanger sequencing on 23 family members for the top candidate gene mutations. We performed parent and sibling-based transmission disequilibrium tests (TDTs) and burden analysis via a penalized linear mixed model, for segregation and mutation burden, respectively. Next, via bioinformatic tools we predicted protein function, mutation pathogenicity, and pathway enrichment to investigate the biological relevance of mutations identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rare missense mutations in\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">KDR\/VEGFR2<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">PDGFRA<\/jats:italic>\n                      showed the best segregation with the OAVS phenotypes in this family. When considering any of the 3 OAVS phenotypes as an outcome,\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      had the strongest associations in parent-TDTs and sib-TDTs (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20090.025,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20090.052) (unadjusted\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      -values). Burden analysis identified\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      (RC\u2009=\u20090.87) and\n                      <jats:italic toggle=\"yes\">PDGFRA<\/jats:italic>\n                      (RC\u2009=\u20090.98) strongly associated with OAVS severity. Using phenotype-specific outcomes, sib-TDTs identified\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      with uni- or bilateral ptosis (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20090.049) and ear tags (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20090.01), and\n                      <jats:italic toggle=\"yes\">PDGFRA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">KDR\/VEGFR2<\/jats:italic>\n                      with ear tags (both\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009&lt;\u20090.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">PDGFRA<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">KDR\/VEGFR2<\/jats:italic>\n                      are strongly associated to OAVS phenotypes.\n                      <jats:italic toggle=\"yes\">SIX1<\/jats:italic>\n                      has been previously associated with OAVS ear malformations and is co-expressed with\n                      <jats:italic toggle=\"yes\">EYA1<\/jats:italic>\n                      during ear development. Efforts to strengthen the genotype-phenotype co-relation underlying the OAVS are key to discover etiology, family counseling, and prevention.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10556656241306202","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T10:27:50Z","timestamp":1737109670000},"page":"562-573","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial Oculoauriculovertebral Spectrum: A Genomic Investigation of Autosomal Dominant Inheritance"],"prefix":"10.1177","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-8120","authenticated-orcid":false,"given":"Aline L","family":"Petrin","sequence":"first","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ligiane Alves","family":"Machado-Paula","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"Hinkle","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Hovey","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Waheed","family":"Awotoye","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Darbro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucilene A","family":"Ribeiro-Bicudo","sequence":"additional","affiliation":[{"name":"Department of Genetics, Universidade Federal de Goias, Goiania, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shareef M","family":"Dabdoub","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tabitha","family":"Peter","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Breheny","sequence":"additional","affiliation":[{"name":"College of Public Health, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey C","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Van Otterloo","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shankar","family":"Rengasamy Venugopalan","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Tufts University School of Dental Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina M","family":"Moreno-Uribe","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1597\/05-060.1"},{"issue":"1","key":"e_1_3_2_3_2","first-page":"56","article-title":"Isolated bilateral macrostomia: literature review and case report","volume":"24","author":"Tarle M","year":"2023","unstructured":"Tarle M, Tarle A, Macan D, Kne\u017eevi\u0107 Krajina H, Kne\u017eevi\u0107 P. 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