Journal article
Genome-wide analysis of copy number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes
American journal of human genetics, Vol.110(1), pp.71-91
01/05/2023
DOI: 10.1016/j.ajhg.2022.11.012
PMCID: PMC9892779
PMID: 36493769
Abstract
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.
Details
- Title: Subtitle
- Genome-wide analysis of copy number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes
- Creators
- Lisa A LansdonAmanda Dickinson - Virginia Commonwealth UniversitySydney Arlis - University of Iowa, BiologyHuan Liu - University of IowaArman Hlas - University of IowaAlyssa Hahn - University of Iowa, Stead Family Department of PediatricsGreg Bonde - University of IowaAbby Long - Department of Biology, University of Iowa, Iowa City, IA 52242, USAJennifer Standley - University of IowaAnastasia Tyryshkina - Pennsylvania State UniversityGeorge Wehby - University of IowaNanette R Lee - University of San CarlosSandra Daack-Hirsch - University of IowaKaren Mohlke - University of North Carolina, Chapel Hill, NC 27514, USASanthosh Girirajan - Pennsylvania State UniversityBenjamin W DarbroRobert A CornellDouglas W HoustonJeffrey C MurrayJ Robert Manak
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.110(1), pp.71-91
- DOI
- 10.1016/j.ajhg.2022.11.012
- PMID
- 36493769
- PMCID
- PMC9892779
- NLM abbreviation
- Am J Hum Genet
- eISSN
- 1537-6605
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 DE-027983, R01 DE-021071, R01 GM-083999, R37 DE-08559, T32 GM-008629
- Language
- English
- Electronic publication date
- 11/30/2022
- Date published
- 01/05/2023
- Academic Unit
- Preventive and Community Dentistry; Health Management and Policy; Medical Genetics and Genomics; Biology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Economics; Orthopedics and Rehabilitation; Fraternal Order of Eagles Diabetes Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984327058202771
Metrics
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