Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate

• Published in: PLoS genetics Vol. 11; no. 3; p. e1005059
• Main Authors: Wolf, Zena T., Brand, Harrison A., Shaffer, John R., Leslie, Elizabeth J., Arzi, Boaz, Willet, Cali E., Cox, Timothy C., McHenry, Toby, Narayan, Nicole, Feingold, Eleanor, Wang, Xioajing, Sliskovic, Saundra, Karmi, Nili, Safra, Noa, Sanchez, Carla, Deleyiannis, Frederic W. B., Murray, Jeffrey C., Wade, Claire M., Marazita, Mary L., Bannasch, Danika L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2015; Public Library of Science (PLoS)
• Subjects: ADAM Proteins - genetics; ADAMTS Proteins; Animals; Birth defects; Brain - abnormalities; Brain - pathology; Cleft lip; Cleft Lip - genetics; Cleft Lip - pathology; Cleft palate; Cleft Palate - genetics; Cleft Palate - pathology; Dogs; Frameshift Mutation; Genes; Genetic aspects; Genetic variation; Genome-wide association studies; Genome-Wide Association Study; Haplotypes; Humans; Identification and classification; Mutation; Polymorphism, Single Nucleotide; Risk factors
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005059

Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.