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Am J Hum Genet 2023 Jan 05;1101:71-91. doi: 10.1016/j.ajhg.2022.11.012.
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Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.

Lansdon LA , Dickinson A , Arlis S , Liu H , Hlas A , Hahn A , Bonde G , Long A , Standley J , Tyryshkina A , Wehby G , Lee NR , Daack-Hirsch S , Mohlke K , Girirajan S , Darbro BW , Cornell RA , Houston DW , Murray JC , Manak JR .

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.

PubMed ID: 36493769
PMC ID: PMC9892779
Article link: Am J Hum Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: arhgef38 cobll1 lpl nhlh1 pkp2 psmd6 ric1
GO keywords: palate development
Morpholinos: arhgef38 MO1 arhgef38 MO2 cobll1 MO1 cobll1 MO2 ric1 MO1 ric1 MO2
gRNAs referenced: arhgef38 gRNA1 arhgef38 gRNA2 cobll1 gRNA1 cobll1 gRNA2 ric1 gRNA1 ric1 gRNA2

Disease Ontology terms: orofacial cleft [+]

Article Images: [+] show captions
References [+] :
Aoyama, Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism. 2017, Pubmed