Molecular Genetic Anatomy and Risk Profile of Hirschsprung’s Disease

作者：Joseph M. Tilghman, Albee Yun Ling, Tychele N. Turner, Maria X. Sosa, Niklas Krumm, Sumantra Chatterjee, Ashish Kapoor, Bradley P. Coe, Khanh-Dung H. Nguyen, Namrata Gupta, Stacey L. Gabriel, Evan E. Eichler, Courtney Berrios, Aravinda Chakravarti · 发表于：New England Journal of Medicine · 年份：2019 · DOI：10.1056/nejmoa1706594 · 被引用次数：200 · 研究领域：Congenital gastrointestinal and neural anomalies、Genomic variations and chromosomal abnormalities、Fetal and Pediatric Neurological Disorders

BACKGROUNDHirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants.The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. METHODSWe genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition.DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder.Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos. RESULTSThe presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval [CI], 3.19 to 6.46).Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58).Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0....