From the Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore (J.M.T., A.Y.L., T.N.T., M.X.S., S.C., A.K., K.-D.H.N., C.B., A.C.); the Department of Genome Sciences, University of Washington School of Medicine (T.N.T., N.K., A.K., B.P.C., E.E.E.), and the Howard Hughes Medical Institute, University of Washington (E.E.E.) - both in Seattle; and Broad Institute of Harvard and MIT, Cambridge, MA (K.-D.H.N., N.G., S.G.).
N Engl J Med. 2019 Apr 11;380(15):1421-1432. doi: 10.1056/NEJMoa1706594.
Hirschsprung'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.
We 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.
The 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 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120).
Among the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with . For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).
先天性巨结肠症（Hirschsprung's disease），又称先天性无神经节细胞症，是一种肠道神经系统发育障碍疾病，是新生儿和婴儿肠梗阻的最常见原因。该疾病的遗传率超过 80%，包括与肠道神经系统相关基因的罕见和常见序列变异，以及与单基因和染色体综合征的显著关联。
我们对 190 名先天性巨结肠症患者的样本进行了基因分型和外显子测序，以量化该疾病患者的遗传负担。先证者的 DNA 序列变异、大片段拷贝数变异和核型变异，如果与先天性巨结肠症或其他神经发育障碍显著相关，则被认为是致病性的。通过在小鼠和人类胚胎肠道以及斑马鱼胚胎中的功能研究来证实新基因。
四个非编码元件中存在五个或更多变异定义了广泛的先天性巨结肠症风险（48.4%的患者和 17.1%的对照；优势比，4.54；95%置信区间[CI]，3.19 至 6.46）。24 个参与肠神经嵴细胞命运的基因中的罕见编码变异，其中 7 个是新的，也很常见（34.7%的患者和 5.0%的对照），并比非编码变异带来更大的风险（优势比，10.02；95%CI，6.45 至 15.58）。大片段拷贝数变异在较少的患者中存在（11.4%，而对照中为 0.2%），但风险最高（优势比，63.07；95%CI，36.75 至 108.25）。在 72.1%的患者中发现了至少一个可识别的遗传风险因素，至少有 48.4%的患者存在编码受体酪氨酸激酶（）的基因的结构或调节缺陷。对于个别患者，先天性巨结肠症的估计风险范围从每 10 万活产儿 5.33 例（约每 18800 例 1 例）到每 1000 例活产儿 8.38 例（约每 120 例 1 例）。
在我们的研究中，患者的先天性巨结肠症是由常见的非编码变异、罕见的编码变异和影响肠神经嵴细胞命运的基因的拷贝数变异引起的，这些变异加剧了与相关的广泛遗传易感性。对于个别患者，基因型特异性优势比相差约 67 倍，这为风险分层和遗传咨询提供了依据。（由美国国立卫生研究院资助）。
