000			03467nab a2200277 4500
999			_c12951 _d12951
003			CO-MdCUR
005			20190726110603.0
007			ta
008			170814s2019 xxu||||| |||| 00| 0 eng d
040			_cRemington _aCO-MdCUR _erda
041			_aeng
082			_221
773	0		_011137 _923480 _aMassachusetts Medical Society _dBoston, Massachusetts Medical Society. _o19653 _tThe New England journal of medicine. _w11137412 _x0028-4793
100	1		_939379 _aTilghman, Joseph M.
245	1		_aMolecular Genetic Anatomy and Risk Profile of Hirschsprung’s Disease
264			_aBoston : _bMassachusetts Medical Society , _c2019
300			_apáginas 1421 - 1432
520	3		_aBACKGROUND 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. METHODS 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. RESULTS 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 (RET). 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). CONCLUSIONS 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 RET. 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.)
650		0	_929547 _aEnfermedad de Hirschsprung
700	1		_939380 _aLing, Albee Y.
700	1		_939381 _aTurner, Tychele N.
942			_2ddc _cHEM