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We analyzed whole genome sequencing data on 419 parent\u2013child trios from the Philippines, a population with a particularly high rate of OFC. To identify novel genes for OFCs, we studied both common variation and de novo variants (DNVs). We identified a significant enrichment in both loss-of-function (N\u2009=\u200962; P\u2009=\u20098.34 \u00d7 10\u22125) and protein-altering DNVs (N\u2009=\u2009394; P\u2009=\u20091.49 \u00d7 10\u22127) among OFC probands. Among the genes individually enriched for DNVs was GRHL2 (P\u2009=\u20096.60 \u00d7 10\u22126), where there were two DNVs, a stop-gain and a frameshift deletion. We then queried OFC trios from other cohorts in the Gabriella Miller Kids First program (total N\u2009=\u20091254) and GeneMatcher and identified an 89\u00a0kb de novo deletion in GRHL2 and a de novo 8q22.3 microdeletion with one breakpoint in GRHL2. Additionally, within the common variant analyses we found significant gene x gene interactions with GRHL2. GRHL2 is a conserved transcription factor involved in embryonic development, with truncating mutations causing autosomal dominant progressive hearing loss and missense variants causing autosomal recessive ectodermal dysplasia. Heterozygous variation in its homolog, GRHL3, causes Van der Woude syndrome and isolated cleft palate. Additionally, mice deficient for either Grhl2 or Grhl3 have craniofacial anomalies, including facial and palatal clefts, strongly supporting GRHL2 as a risk locus for OFCs.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf163","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T11:25:55Z","timestamp":1761045955000},"page":"2088-2098","source":"Crossref","is-referenced-by-count":1,"title":["Haploinsufficiency of\n                    <i>GRHL2<\/i>\n                    is associated with orofacial clefting in humans"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9131-9601","authenticated-orcid":false,"given":"Sarah W","family":"Curtis","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , 615 Michael Street, Suite 301 Atlanta, GA 30322 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinderella","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , 615 Michael Street, Suite 301 Atlanta, GA 30322 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Sanchis-Juan","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , 185 Cambridge Street, Boston, MA 02114 ,","place":["United States"]},{"name":"Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard , 415 Main St., Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Singleton","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , 615 Michael Street, Suite 301 Atlanta, GA 30322 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri H","family":"Beaty","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins University , 615 North Wolfe Street, Baltimore, MD 21205 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Erger","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne , Kerpener Stra\u00dfe 34, 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-9738","authenticated-orcid":false,"given":"Michael P","family":"Epstein","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine , 615 Michael Street, Suite 301 Atlanta, GA 30322 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh , 3501 Terrace Street, Pittsburgh, PA 15261 ,","place":["United States"]},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh , 130 De Soto Street, Pittsburgh, PA 15261 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Krause","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne , Kerpener Stra\u00dfe 34, 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M","family":"Moreno Uribe","sequence":"additional","affiliation":[{"name":"The Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa , 801 Newton Rd., Iowa City, IA 52242 ,","place":["United States"]},{"name":"Department of Orthodontics, College of Dentistry, University of Iowa , 801 Newton Rd., Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Netzer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne , Kerpener Stra\u00dfe 34, 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmencita D","family":"Padilla","sequence":"additional","affiliation":[{"name":"College of Medicine, University of the Philippines Manila , 547 Pedro Gil Street, Ermita Manila ,","place":["Philippines"]},{"name":"Newborn Screening Reference Center, National Institutes of Health (Philippines) , 1579 F.T. Benitez St., Malate Manila,","place":["Philippines"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh , 3501 Terrace Street, Pittsburgh, PA 15261 ,","place":["United States"]},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh , 130 De Soto Street, Pittsburgh, PA 15261 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh , 3501 Terrace Street, Pittsburgh, PA 15261 ,","place":["United States"]},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh , 130 De Soto Street, Pittsburgh, PA 15261 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-0833","authenticated-orcid":false,"given":"Jenna C","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh , 130 De Soto Street, Pittsburgh, PA 15261 ,","place":["United States"]},{"name":"Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh , 130 De Soto Street, Pittsburgh, PA 15261 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Velmans","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne , Kerpener Stra\u00dfe 34, 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Iowa , 200 Hawkins Drive, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seb","family":"Dworkin","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University , Plenty Road, Bundoora, VIC 3086 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L","family":"Marazita","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh , 3501 Terrace Street, Pittsburgh, PA 15261 ,","place":["United States"]},{"name":"Department of Human Genetics, School of Public Health, University of 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