title: Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.
abstract: 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.
authors: Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
authors: Zena T
authors: ZT
authors: Wolf
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors: Harrison A
authors: HA
authors: Brand
authors: Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors: John R
authors: JR
authors: Shaffer
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Elizabeth J
authors: EJ
authors: Leslie
authors: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.
authors: Boaz
authors: B
authors: Arzi
authors: Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia.
authors: Cali E
authors: CE
authors: Willet
authors: Department of Pediatrics (Division of Craniofacial Medicine), University of Washington, Seattle, Washington, United States of America; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, United States of America; Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors: Timothy C
authors: TC
authors: Cox
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Toby
authors: T
authors: McHenry
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Nicole
authors: N
authors: Narayan
authors: Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors: Eleanor
authors: E
authors: Feingold
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Xioajing
authors: X
authors: Wang
authors: Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
authors: Saundra
authors: S
authors: Sliskovic
authors: Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
authors: Nili
authors: N
authors: Karmi
authors: Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
authors: Noa
authors: N
authors: Safra
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Carla
authors: C
authors: Sanchez
authors: Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors: Frederic W B
authors: FW
authors: Deleyiannis
authors: Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
authors: Jeffrey C
authors: JC
authors: Murray
authors: Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia.
authors: Claire M
authors: CM
authors: Wade
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America; Clinical and Translational Science and Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Mary L
authors: ML
authors: Marazita
authors: Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
authors: Danika L
authors: DL
authors: Bannasch
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D016368:Frameshift Mutation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C473773:ADAMTS20 protein, human