{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:09:26Z","timestamp":1785409766971,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01-DE031261 (H.B.), R01-DE030342 (E.J.L-C.), R01-DE028342 (E.J.L-C.), T32-HG010464-06 (A.S-J.), R01HD081256 (M.E.T.), U01-HG011755 (M.E.T.), F31-DE032588 (K.R.R.), R01-DE0332319 (M.L.M.), R01-DE028300 (A.B.), R01DE011931 (J.T.H.), X01-HL0132363 (M.L.M.), X01-HL136998 (M.L.M.), X01-HL140535 (A.B., T.H.B.), X01-HG010835 (E.J.L.-C.), X01-HD100701 (E.J.L-C.), X01-DE030062 (M.L.M.)"],"award-info":[{"award-number":["R01-DE031261 (H.B.), R01-DE030342 (E.J.L-C.), R01-DE028342 (E.J.L-C.), T32-HG010464-06 (A.S-J.), R01HD081256 (M.E.T.), U01-HG011755 (M.E.T.), F31-DE032588 (K.R.R.), R01-DE0332319 (M.L.M.), R01-DE028300 (A.B.), R01DE011931 (J.T.H.), X01-HL0132363 (M.L.M.), X01-HL136998 (M.L.M.), X01-HL140535 (A.B., T.H.B.), X01-HG010835 (E.J.L.-C.), X01-HD100701 (E.J.L-C.), X01-DE030062 (M.L.M.)"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Orofacial clefts (OFCs) and other palate abnormalities (PAs) are among the most common birth defects worldwide and are characterized by the abnormal formation of the lip and\/or palate. Genetic studies have traditionally classified OFC cases as either syndromic, involving OFCs alongside other congenital anomalies, or nonsyndromic, which represent the majority of cases and occur in isolation. Emerging genomic evidence indicates that genes traditionally associated with syndromic forms of OFC can also harbor variants contributing to isolated cases, challenging the notion of a strict dichotomy between these categories and supporting their integration for gene discovery.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this study, we applied multiple analytic approaches to characterize the genetic architecture of OFC and PAs by integrating genomic data from 2,497 trios with probands diagnosed with an OFC (n=2,080) or PA (n=417). We compared these findings across OFC subtypes and syndromic status with those from 5,515 control trios to identify enriched biological pathways and mechanisms and to prioritize candidate genes using variant burden testing.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We observed a significant enrichment of\n                    <jats:italic>de novo<\/jats:italic>\n                    protein-truncating and damaging missense variants in cases compared to controls (OR = 2.17, p = 1.21x10\n                    <jats:sup>-32<\/jats:sup>\n                    ), with particularly strong signals in biologically relevant gene sets involving OFC-associated, constrained, Mendelian disorder, and mouse candidate genes. Variant burden testing identified 39 OFC risk genes at FDR \u2264 0.05, which we then integrated with 593 established OFC genes to interrogate the functional underpinnings of OFC via network analysis. This analysis revealed 309 high-order interactor genes not previously associated with OFC. Notably, this OFC network clustered into ten distinct biological pathways, with nucleosome-associated genes showing significant enrichment among cases in our cohort (OR = 14.8, p = 8.1x10\n                    <jats:sup>-4<\/jats:sup>\n                    ). In a final integrative step, we combined evidence across all analyses to nominate 231 candidate genes, 32 of which contained at least two deleterious\n                    <jats:italic>de novo<\/jats:italic>\n                    variants in our cohort.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings underscore the value of integrating diverse OFC and PA subtypes, syndromic status, and variant classes to elucidate the genetic architecture of these disorders, highlighting both phenotypic expansion of known disease genes and the emergence of novel gene-phenotype associations.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.21.26352934","type":"posted-content","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T03:05:12Z","timestamp":1779678312000},"source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive analysis of\n                  <i>de novo<\/i>\n                  variants across 2,497 orofacial cleft trios reveals novel genetic drivers of disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8498-3400","authenticated-orcid":false,"given":"Nehir E.","family":"Kurtas","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2788-5497","authenticated-orcid":false,"given":"Alba","family":"Sanchis-Juan","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eren","family":"Shin","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah W.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey R.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeez A.","family":"Alade","sequence":"additional","affiliation":[{"name":"Iowa Institute of Oral Health Research, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Fu","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly K.","family":"Diaz Perez","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lord J. J.","family":"Gowans","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mekonen A.","family":"Eshete","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasiu L.","family":"Adeyemo","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos\/Lagos University Teaching Hospital, Lagos, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen J.","family":"Bux\u00f3","sequence":"additional","affiliation":[{"name":"Dental and Craniofacial Genomics Core, University of Puerto Rico School of Dental Medicine, San Juan, Puerto Rico, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Hecht","sequence":"additional","affiliation":[{"name":"McGovern Medical School University of Texas Health Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M.","family":"Moreno Uribe","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandita","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA"}],"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, Pittsburgh, PA, USA"},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins University, Baltimore, MD, 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