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 human...伴或不伴腭裂的唇裂（Cleft lip with or without cleft palate, CL/P）是最为常见的颅面出生缺陷（craniofacial birth defect）。本研究通过对犬类与人类两个物种开展全基因组关联研究（genome-wide association studies），阐明该出生缺陷的遗传病因学机制。在犬类研究中，针对来自新斯科舍猎鸭寻回犬（Nova Scotia Duck Tolling Retriever, NSDTR）品种的7例CL/P病例与112例对照开展全基因组关联研究，在犬27号染色体上鉴定出一个显著关联的基因组区域（未校正p值为1.1×10⁻¹³；校正后p值为2.2×10⁻³）。对NSDTR家系及额外全同胞病例的进一步分析显示，一段位于27号染色体9.29–10.73 Mb的1.44 Mb纯合单倍型（homozygous haplotype），与13例病例中呈现的唇裂、腭裂并指综合征（cleft lip, cleft palate, and syndactyly, CLPS）复杂表型共分离。对3例CLPS病例与4例对照开展15倍覆盖度的全基因组测序（whole-genome sequencing），成功鉴定出ADAMTS20基因内的一处移码突变（frameshift mutation，c.1360_1361delAA，p.Lys453Ilefs*3），该突变与表型共分离。在平行开展的人类研究中……