Evidence map›Paper›PMID 30970187›Full record

ArticleThe New England journal of medicine2019

Molecular Genetic Anatomy and Risk Profile of Hirschsprung's Disease.

Joseph M Tilghman, Albee Y Ling, Tychele N Turner, Maria X Sosa, Niklas Krumm, Sumantra Chatterjee, Ashish Kapoor, Bradley P Coe, Khanh-Dung H Nguyen, Namrata Gupta and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The New England journal of medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
106citing papers in PubMed, 4 pooled it
23.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

106 citing papers in PubMed, 4 syntheses or guidelines pooled it, 187 citations in OpenAlex.

  1. Pooled it
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  6. Review
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  17. Aberrant Expressions ofCurrent pediatric reviews · 2026
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  18. Review
  19. Joint disruption ofProceedings of the National Academy of Sciences of the United States of America · 2025
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  20. Article

46 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors at 2 institutions in 1 country.

Joseph M TilghmanFrom 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.).
Albee Y LingFrom 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.).
Tychele N TurnerFrom 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.).
Maria X SosaFrom 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.).
Niklas KrummFrom 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.).
Sumantra ChatterjeeFrom 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.).
Ashish KapoorFrom 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.).
Bradley P CoeFrom 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.).
Khanh-Dung H NguyenFrom 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.).
Namrata GuptaFrom 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.).
Stacey GabrielFrom 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.).
Evan E EichlerFrom 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.).ORCID 0000-0002-8246-4014
Courtney BerriosFrom 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.).
Aravinda ChakravartiFrom 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.).
Howard Hughes Medical Institute · USBroad Institute · US

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
Predoctoral Training Program in Human GeneticsT32GM007814 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 1985 to 2021
$10.6M
Sporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2M
Genetic Analysis of Hirschsprung Disease - RenewalR01HD028088 · NICHD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAKRAVARTI, ARAVINDA · 1991 to 2024
$6.2M
Genetic Analysis of Hirschsprung DiseaseR37HD028088 · NICHD · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI CHAKRAVARTI, ARAVINDA · 2010 to 2019
$6.2M
Medical Research Council MR/R006237/1NHGRI NIH HHS U54 HG003067NICHD NIH HHS R01 HD028088NICHD NIH HHS R37 HD028088NIGMS NIH HHS T32 GM007814NIH HHS R37 HD28088NIH HHS U54 HG003067NIMH NIH HHS R01 MH101221
6 · The paper itself

Abstract

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 0.2% 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 (

conclusionsAmong 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

Indexed as

Genetic VariationGenotypeExomeExome SequencingFemaleGenetic Predisposition to DiseaseHirschsprung DiseaseHumansMaleMutationOdds RatioPenetranceSequence Analysis, DNA

Identifiers

PMID30970187
PMCPMC6596298
OpenAlexW2940312081

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.