PUBLICATION
Genome-wide analysis of copy number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes
- Authors
- Lansdon, L.A., Dickinson, A., Arlis, S., Liu, H., Hlas, A., Hahn, A., Bonde, G., Long, A., Standley, J., Tyryshkina, A., Wehby, G., Lee, N.R., Daack-Hirsch, S., Mohlke, K., Girirajan, S., Darbro, B.W., Cornell, R.A., Houston, D.W., Murray, J.C., Manak, J.R.
- ID
- ZDB-PUB-221210-9
- Date
- 2022
- Source
- American journal of human genetics 110(1): 71-91 (Journal)
- Registered Authors
- Bonde, Greg, Cornell, Robert
- Keywords
- ARHGEF38, COBLL1, Danio rerio, RIC1, Xenopus laevis, cleft lip and palate, congenital anomalies, copy number variants, craniofacial
- MeSH Terms
-
- Cleft Lip*/genetics
- Cleft Palate*/genetics
- DNA Copy Number Variations*
- Genome-Wide Association Study
- Guanine Nucleotide Exchange Factors/genetics
- Humans
- Phenotype
- Transcription Factors/genetics
- PubMed
- 36493769 Full text @ Am. J. Hum. Genet.
Citation
Lansdon, L.A., Dickinson, A., Arlis, S., Liu, H., Hlas, A., Hahn, A., Bonde, G., Long, A., Standley, J., Tyryshkina, A., Wehby, G., Lee, N.R., Daack-Hirsch, S., Mohlke, K., Girirajan, S., Darbro, B.W., Cornell, R.A., Houston, D.W., Murray, J.C., Manak, J.R. (2022) 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. 110(1):71-91.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping