{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T07:37:05Z","timestamp":1783409825114,"version":"3.54.6"},"reference-count":16,"publisher":"BMJ","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:sec>\n                  <jats:title>Background:<\/jats:title>\n                  <jats:p>Hirschsprung disease (HSCR) is a developmental disorder caused by a defect in the neural crest neuroblast migration process. It is considered to be a paradigm of complex disorders, with many loci contributing to manifestation of the disease. Although HSCR commonly appears as a sporadic trait, \u223c20% of HSCR cases are familial, with complex patterns of inheritance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Method:<\/jats:title>\n                  <jats:p>A multiplex HSCR family with an additive model of inheritance, in which the contribution of three genes (<jats:italic>RET, NTRK3, EDN3<\/jats:italic>) leads to the HSCR phenotype is reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results and discussion:<\/jats:title>\n                  <jats:p>The findings suggest that both <jats:italic>RET<\/jats:italic> and <jats:italic>NTRK3<\/jats:italic> mutations acting together are necessary and sufficient for the appearance of the disease, and that the <jats:italic>EDN3<\/jats:italic> mutation is acting as a phenotype-modifier factor in the context of this family, as two different HSCR phenotypes are seen among the affected members: a short segment form, and a total colonic aganglionosis. The results therefore support the complex additive model of inheritance previously proposed for Hirschsprung disease.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2009.067819","type":"journal-article","created":{"date-parts":[[2009,6,26]],"date-time":"2009-06-26T20:13:00Z","timestamp":1246047180000},"page":"862-864","source":"Crossref","is-referenced-by-count":20,"title":["Contribution of <i>RET, NTRK3<\/i> and <i>EDN3<\/i> to the expression of Hirschsprung disease in a multiplex family: Figure 1"],"prefix":"10.1136","volume":"46","author":[{"given":"A","family":"S\u00e1nchez-Mej\u00edas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R M","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"L\u00f3pez-Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Anti\u00f1olo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Borrego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2009,6,25]]},"reference":[{"key":"2025100521043321000_46.12.862.1","unstructured":"Chakravarti A Lyonnet S . Hirschsprung disease. In: Scriver CS , ed. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2002:6231\u00e2\u0080\u009355."},{"key":"2025100521043321000_46.12.862.2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.053959"},{"key":"2025100521043321000_46.12.862.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.268"},{"key":"2025100521043321000_46.12.862.4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/ng868","article-title":"Segregation at three loci explains familial and population risk in Hirschsprung disease.","volume":"31","author":"Gabriel","year":"2002","journal-title":"Nat Genet"},{"key":"2025100521043321000_46.12.862.5","first-page":"303","article-title":"Endothelin receptor-mediated signaling in Hirschsprung disease.","volume":"5","author":"Chakravarti","year":"1996","journal-title":"Hum Mol Genet"},{"key":"2025100521043321000_46.12.862.6","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1242\/dev.126.6.1161","article-title":"Inhibition of in vitro enteric neuronal development by endothelin-3: mediation by endothelin B receptors.","volume":"126","author":"Wu","year":"1999","journal-title":"Development"},{"key":"2025100521043321000_46.12.862.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.03.031"},{"key":"2025100521043321000_46.12.862.8","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-442"},{"key":"2025100521043321000_46.12.862.9","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-445"},{"key":"2025100521043321000_46.12.862.10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000484771","article-title":"Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease.","volume":"5","author":"Bidaud","year":"1997","journal-title":"Eur J Hum Genet"},{"key":"2025100521043321000_46.12.862.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2008.02.076"},{"key":"2025100521043321000_46.12.862.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2008.00479.x"},{"key":"2025100521043321000_46.12.862.13","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1097\/01.gim.0000245632.06064.f1","article-title":"A complex additive model of inheritance for HSCR is supported by both RET mutations and predisposing RET haplotypes.","volume":"8","author":"Ruiz-Ferrer","year":"2006","journal-title":"Genet Med"},{"key":"2025100521043321000_46.12.862.14","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2168.2000.01401.x"},{"key":"2025100521043321000_46.12.862.15","doi-asserted-by":"publisher","DOI":"10.1038\/ng0896-395"},{"key":"2025100521043321000_46.12.862.16","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0079-6123(03)46016-0","article-title":"Neurotrophin-3 in the developmenrt of the enteric nervous system.","volume":"146","author":"Chalazonitis","year":"2004","journal-title":"Prog Brain Res"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.2009.067819","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T04:04:39Z","timestamp":1759723479000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.2009.067819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,6,25]]},"references-count":16,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,12,1]]},"published-print":{"date-parts":[[2009,12]]}},"alternative-id":["10.1136\/jmg.2009.067819"],"URL":"https:\/\/doi.org\/10.1136\/jmg.2009.067819","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,6,25]]}}}