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

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.