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PLoS Genet. 2015 Mar 23;11(3):e1005059. doi: 10.1371/journal.pgen.1005059. eCollection 2015 Mar.

Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.

Author information

1
Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.
2
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.
3
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
4
Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
5
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.
6
Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia.
7
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.
8
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
9
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
10
Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
11
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.

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.

PMID:
25798845
PMCID:
PMC4370697
DOI:
10.1371/journal.pgen.1005059
[Indexed for MEDLINE]
Free PMC Article

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