PLoS Genetics (Mar 2015)

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

  • Zena T Wolf,
  • Harrison A Brand,
  • John R Shaffer,
  • Elizabeth J Leslie,
  • Boaz Arzi,
  • Cali E Willet,
  • Timothy C Cox,
  • Toby McHenry,
  • Nicole Narayan,
  • Eleanor Feingold,
  • Xioajing Wang,
  • Saundra Sliskovic,
  • Nili Karmi,
  • Noa Safra,
  • Carla Sanchez,
  • Frederic W B Deleyiannis,
  • Jeffrey C Murray,
  • Claire M Wade,
  • Mary L Marazita,
  • Danika L Bannasch

DOI
https://doi.org/10.1371/journal.pgen.1005059
Journal volume & issue
Vol. 11, no. 3
p. e1005059

Abstract

Read online

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.