Parallel Studies in Humans and Dogs Implicate ADAMTS20 in Cleft Lip and Palate Formation. Z. Wolf1, B. Arzi2, E. Leslie3, J. Shaffer4, H. Brand3,4, C. Willet5, N. Karmi1, T. McHenry3, E. Feingold4, X. Wang3, J. Murray6, M. Marazita3,7, C. Wade5, D. Bannasch1 1) Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA; 2) Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA; 3) Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA; 4) Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; 5) Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia; 6) Department of Pediatrics, University of Iowa, Iowa City, IA; 7) Clinical and Translational Science and Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA.

   Cleft lip with or without cleft palate (CL/P) and cleft palate (CP) are commonly occurring birth defects in people. In order to better elucidate the molecular mechanisms responsible for formation of these birth defects, we utilized the domestic dog. Much like human orofacial clefts, CL/P and CP in dogs are naturally occurring, genetically heterogeneous, and follow the highly conserved steps of palatal development. Notably, the population structure of purebred dogs provides a powerful resource to study a complex trait on a simple genetic background. Previous work in dogs investigating DLX5 and DLX6 as candidate genes identified a LINE-1 insertion within DLX6 in 12 CP cases from the Nova Scotia Duck Tolling Retriever (NSDTR) breed. This prompted the sequencing of the same candidate genes in a cohort of 197 humans with CL/P or CP, where a missense mutation in the highly conserved functional domain of DLX5 was identified in one of 30 patients with Pierre Robin Sequence (Wolf, Leslie et al. 2014). Since DLX5/6 only explain one human and 12 of 22 NSDTRs with orofacial clefts, we performed a genome-wide association study (GWAS) in 7 CL/P cases and 112 controls within NSDTRs to identify additional genes involved in orofacial cleft formation. This GWAS identified an associated region on canine chromosome 27 (9.29 - 10.73 Mb) and whole-genome sequencing of 3 cases and 4 controls identified a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)) that is predicted to truncate 75% of the functional protein. A parallel study in a human cohort of 937 Guatemalans (545 from CL/P case families and 392 controls) also identified allelic (p =2.67 x 10-6) and gene-level (p=5.3 x 10-5) associations within ADAMTS20, further implicating ADAMTS20 in CL/P formation. DLX5/6 and ADAMTS20 only explain 20 of the 22 NSDTR cases, leaving additional loci to be identified. Overall, these results demonstrate the power of the canine animal model as a genetically tractable approach to understanding naturally occurring and heterogeneous birth defects in humans.

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