Academic Journal
Comprehensive analysis of de novo variants across 2,497 orofacial cleft trios reveals novel genetic drivers of disease.
| Τίτλος: | Comprehensive analysis of de novo variants across 2,497 orofacial cleft trios reveals novel genetic drivers of disease. |
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| Συγγραφείς: | Kurtas NE; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Sanchis-Juan A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Shin E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Curtis SW; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Robinson KR; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Lee AS; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Alade AA; Iowa Institute of Oral Health Research, University of Iowa, Iowa City, IA, USA., Zhao X; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Fu J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Diaz Perez KK; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Gowans LJJ; Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana., Eshete MA; Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia., Adeyemo WL; Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria., Buxó CJ; Dental and Craniofacial Genomics Core, University of Puerto Rico School of Dental Medicine, San Juan, Puerto Rico, USA., Padilla CD; Department of Pediatrics, College of Medicine, University of the Philippines, Manila, Philippines., Poletta FA; CEMIC-CONICET: Center for Medical Education and Clinical Research, Buenos Aires, Argentina., Torres AC; European Genome-Phenome Archive at the Center for Genomic Regulation, Barcelona, Spain., Wehby GL; Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, USA., Hecht JT; McGovern Medical School University of Texas Health Houston, Houston, TX, USA., Moreno Uribe LM; Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA., Mukhopadhyay N; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Shaffer JR; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA., Weinberg SM; Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina, Chapel Hill, NC, USA., Murray JC; Department of Pediatrics, School of Medicine, University of Iowa, Iowa City, IA, USA., Beaty TH; Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA., Butali A; Iowa Institute of Oral Health Research, University of Iowa, Iowa City, IA, USA., Talkowski M; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA., Leslie-Clarkson EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. |
| Πηγή: | MedRxiv : the preprint server for health sciences [medRxiv] 2026 May 24. Date of Electronic Publication: 2026 May 24. |
| Τύπος έκδοσης: | Journal Article; Preprint |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Περίληψη: | Background: 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. Methods: 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. Results: We observed a significant enrichment of de novo protein-truncating and damaging missense variants in cases compared to controls (OR = 2.17, p = 1.21×10-32), 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 ≤ 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 = 8.1×10-4). In a final integrative step, we combined evidence across all analyses to nominate 231 candidate genes, 32 of which contained at least two deleterious de novo variants in our cohort. Conclusions: 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. |
| Competing Interests: | Competing interests The authors declare that they have no competing interests. |
| References: | PLoS Comput Biol. 2015 Dec 01;11(12):e1004572. (PMID: 26625158) Front Genet. 2022 Feb 24;13:828534. (PMID: 35281813) Am J Hum Genet. 2016 Apr 7;98(4):744-54. (PMID: 27018472) PLoS Genet. 2013;9(8):e1003671. (PMID: 23966865) Annu Rev Genomics Hum Genet. 2012;13:263-83. (PMID: 22703175) Sci Rep. 2021 Apr 6;11(1):7556. (PMID: 33824370) Wiley Interdiscip Rev Syst Biol Med. 2009 Nov-Dec;1(3):390-399. (PMID: 20052305) Mol Genet Genomic Med. 2017 Jan 17;5(1):3-7. (PMID: 28116324) Science. 2018 Dec 14;362(6420):. (PMID: 30545852) Front Oral Biol. 2012;16:1-18. (PMID: 22759666) Hum Mol Genet. 2003 Oct 1;12(19):2491-501. (PMID: 12915443) Nat Genet. 2022 Sep;54(9):1320-1331. (PMID: 35982160) Front Pediatr. 2023 Mar 20;11:967701. (PMID: 37020656) Nat Genet. 2002 Oct;32(2):285-9. (PMID: 12219090) Genet Med. 2023 Oct;25(10):100918. (PMID: 37330696) HGG Adv. 2021 Jun 08;2(3):100038. (PMID: 35047836) Birth Defects Res A Clin Mol Teratol. 2011 Feb;91(2):85-92. (PMID: 21319277) Cells. 2025 Jun 17;14(12):. (PMID: 40558542) Genome Med. 2020 Jul 14;12(1):62. (PMID: 32664994) Nat Commun. 2017 Feb 24;8:14364. (PMID: 28232668) Birth Defects Res. 2025 Jul;117(7):e2499. (PMID: 40631876) Genome Res. 2017 Nov;27(11):1916-1929. (PMID: 28855259) Nucleic Acids Res. 2015 Jan;43(Database issue):D789-98. (PMID: 25428349) Am J Hum Genet. 2016 Jan 7;98(1):127-48. (PMID: 26748516) OMICS. 2012 May;16(5):284-7. (PMID: 22455463) Am J Hum Genet. 2025 Nov 6;112(11):2679-2692. (PMID: 41056948) Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199) Am J Med Genet C Semin Med Genet. 2013 Nov;163C(4):246-58. (PMID: 24124047) Genet Epidemiol. 2024 Sep;48(6):258-269. (PMID: 38634654) Nature. 2020 May;581(7809):434-443. (PMID: 32461654) Nat Genet. 2023 Sep;55(9):1589-1597. (PMID: 37604963) Clin Genet. 2016 Jul;90(1):28-34. (PMID: 26346622) Am J Med Genet A. 2015 Sep;167A(9):2182-7. (PMID: 25929198) Nucleic Acids Res. 2024 Jan 5;52(D1):D1333-D1346. (PMID: 37953324) BMC Oral Health. 2025 Jan 22;25(1):114. (PMID: 39844198) Nucleic Acids Res. 2011 Jan;39(Database issue):D52-7. (PMID: 21115458) Nat Genet. 2016 Sep;48(9):1060-5. (PMID: 27479907) Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651) Nucleic Acids Res. 2025 Jan 6;53(D1):D998-D1005. (PMID: 39530240) Birth Defects Res. 2024 Jan;116(1):e2301. (PMID: 38277408) Nucleic Acids Res. 2024 Jan 5;52(D1):D891-D899. (PMID: 37953337) Nucleic Acids Res. 2012 May;40(9):e69. (PMID: 22302147) Bioinformatics. 2016 Apr 15;32(8):1220-2. (PMID: 26647377) Nature. 2020 May;581(7809):444-451. (PMID: 32461652) Nucleic Acids Res. 2023 Jan 6;51(D1):D638-D646. (PMID: 36370105) Bioinformatics. 2015 May 1;31(9):1375-81. (PMID: 25535243) Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658) J Med Genet. 2018 Jul;55(7):449-458. (PMID: 29500247) Neuron. 2015 Sep 23;87(6):1215-1233. (PMID: 26402605) Mol Syndromol. 2010;1(2):67-74. (PMID: 21045959) HGG Adv. 2022 Dec 05;4(1):100166. (PMID: 36589413) Am J Med Genet A. 2020 Jan;182(1):25-28. (PMID: 31710778) Children (Basel). 2024 Mar 08;11(3):. (PMID: 38539356) Hum Genomics. 2025 Apr 29;19(1):47. (PMID: 40301961) Nature. 2020 Oct;586(7831):757-762. (PMID: 33057194) Hum Genet. 2017 Mar;136(3):275-286. (PMID: 28054174) Am J Hum Genet. 2021 Apr 1;108(4):597-607. (PMID: 33675682) Nucleic Acids Res. 2026 Jan 6;54(D1):D1779-D1792. (PMID: 41413728) Am J Hum Genet. 2012 Aug 10;91(2):358-64. (PMID: 22795537) Nat Biotechnol. 2011 Jan;29(1):24-6. (PMID: 21221095) Nat Genet. 2018 May;50(5):727-736. (PMID: 29700473) Cleft Palate Craniofac J. 2021 Jan;58(1):54-60. (PMID: 32602363) Cleft Palate J. 1988 Jan;25(1):16-20. (PMID: 3422594) Hum Mol Genet. 2023 May 18;32(11):1932-1942. (PMID: 37010288) Genet Med. 2013 May;15(5):338-44. (PMID: 23154523) Birth Defects Res. 2024 Jan;116(1):e2271. (PMID: 37964651) Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278) Mol Genet Genomic Med. 2014 May;2(3):254-60. (PMID: 24936515) Am J Hum Genet. 2020 Jul 2;107(1):124-136. (PMID: 32574564) NPJ Genom Med. 2025 Sep 29;10(1):63. (PMID: 41022857) Sci Rep. 2024 Nov 3;14(1):26492. (PMID: 39489835) Nat Rev Genet. 2011 Mar;12(3):167-78. (PMID: 21331089) Biol Psychiatry. 2019 Feb 15;85(4):287-297. (PMID: 29724491) |
| Grant Information: | U54 NS108251 United States NS NINDS NIH HHS; R01 DE011931 United States DE NIDCR NIH HHS; U01 HG010219 United States HG NHGRI NIH HHS; U01 NS134353 United States NS NINDS NIH HHS; R01 DE030342 United States DE NIDCR NIH HHS; U01 HG011745 United States HG NHGRI NIH HHS; U01 HG011762 United States HG NHGRI NIH HHS; U01 HG010233 United States HG NHGRI NIH HHS; R01 HD081256 United States HD NICHD NIH HHS; U01 HG011755 United States HG NHGRI NIH HHS; U01 HG010217 United States HG NHGRI NIH HHS; United Kingdom WT_ Wellcome Trust; U01 NS134350 United States NS NINDS NIH HHS; U01 NS134358 United States NS NINDS NIH HHS; U01 HG007690 United States HG NHGRI NIH HHS; U01 NS134354 United States NS NINDS NIH HHS; U54 HG006542 United States HG NHGRI NIH HHS; U01 NS134357 United States NS NINDS NIH HHS; U24 HG011746 United States HG NHGRI NIH HHS; U01 NS134348 United States NS NINDS NIH HHS; U2C NS132415 United States NS NINDS NIH HHS; T32 HG010464 United States HG NHGRI NIH HHS; U01 HG010215 United States HG NHGRI NIH HHS; U01 HG007708 United States HG NHGRI NIH HHS; U01 HG007674 United States HG NHGRI NIH HHS; U01 NS134356 United States NS NINDS NIH HHS; U01 HG007672 United States HG NHGRI NIH HHS; U01 NS134349 United States NS NINDS NIH HHS; U01 NS134352 United States NS NINDS NIH HHS; U01 TR001395 United States TR NCATS NIH HHS; U01 HG007709 United States HG NHGRI NIH HHS; U01 HG010230 United States HG NHGRI NIH HHS; U01 HG011744 United States HG NHGRI NIH HHS; R01 DE028300 United States DE NIDCR NIH HHS; U01 NS134355 United States NS NINDS NIH HHS; U01 HG007943 United States HG NHGRI NIH HHS; R01 DE031261 United States DE NIDCR NIH HHS; U54 NS093793 United States NS NINDS NIH HHS; U01 NS134351 United States NS NINDS NIH HHS; U01 HG007530 United States HG NHGRI NIH HHS; U01 TR002471 United States TR NCATS NIH HHS; U01 HG007703 United States HG NHGRI NIH HHS; U01 HG007942 United States HG NHGRI NIH HHS; R01 DE028342 United States DE NIDCR NIH HHS; F31 DE032588 United States DE NIDCR NIH HHS; U01 HG011758 United States HG NHGRI NIH HHS |
| Contributed Indexing: | Keywords: De Novo Variant Enrichment; Genetic Analysis; Genomic Sequencing; Orofacial Clefting; Palate Abnormalities; Structural variants; Variant Burden Testing |
| Entry Date(s): | Date Created: 20260604 Date Completed: 20260914 Latest Revision: 20260922 |
| Update Code: | 20260922 |
| PubMed Central ID: | PMC13228697 |
| DOI: | 10.64898/2026.05.21.26352934 |
| PMID: | 42238460 |
| Βάση Δεδομένων: | MEDLINE |
| DOI: | 10.64898/2026.05.21.26352934 |
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