Lisa A. Lansdon, Amanda Dickinson, Sydney Arlis, Huan Liu, Arman Hlas, Alyssa Hahn, Greg Bonde, Abby Long, Jennifer Standley, Anastasia Tyryshkina, George Wehby, Nanette R. Lee, Sandra Daack-Hirsch, Karen Mohlke, Santhosh Girirajan, Benjamin W. Darbro, Robert A. Cornell, Douglas W. Houston, Jeffrey C. Murray, J. Robert Manak
Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders. © 2022 American Society of Human Genetics
Department of Pediatrics, University of Iowa, Iowa City, 52242, IA, United States; Department of Biology, University of Iowa, Iowa City, 52242, IA, United States; Interdisciplinary Genetics Program, University of Iowa, Iowa City, 52242, IA, United States; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, 64108, MO, United States; Department of Pathology, University of Missouri – Kansas City School of Medicine, Kansas City, 64108, MO, United States; Virginia Commonwealth University, Richmond, 23284, VA, United States; Department of Anatomy and Cell Biology, University of Iowa, Iowa City, 52242, IA, United States; Pennsylvania State University, University Park, 16802, PA, United States; College of Public Health, University of Iowa, Iowa City, 52242, IA, United States; Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines; College of Nursing, University of Iowa, Iowa City, 52242, IA, United States; University of North Carolina, Chapel Hill, 27514, NC, United States
