Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting.

Autor:	Diaz Perez KK; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Curtis SW; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Sanchis-Juan A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, Department of Neurology and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA., Zhao X; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, Department of Neurology and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA., Head T; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA., Ho S; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Carter B; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA; Agnes Scott College, Decatur, GA., McHenry T; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA., Bishop MR; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Valencia-Ramirez LC; Fundación Clinica Noel, Medellin, Colombia., Restrepo C; Fundación Clinica Noel, Medellin, Colombia., Hecht JT; Department of Pediatrics, McGovern Medical, School and School of Dentistry, UT Health at Houston, Houston, TX., Uribe LM; Department of Orthodontics, University of Iowa, Iowa City, IA., Wehby G; Department of Health Management and Policy, University of Iowa, Iowa City, IA., Weinberg SM; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA., Beaty TH; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD., Murray JC; Department of Pediatrics, University of Iowa, Iowa City, IA., Feingold E; Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA; Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA., Cutler DJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Epstein MP; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA., Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, Department of Neurology and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA., Leslie EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA. Electronic address: ejlesli@emory.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Oct; Vol. 25 (10), pp. 100918. Date of Electronic Publication: 2023 Jun 15.
DOI:	10.1016/j.gim.2023.100918
Abstrakt:	Purpose: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. Methods: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. Results: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance. Conclusion: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs. Competing Interests: Conflict of Interest The authors declare no conflicts of interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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