{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:12:29Z","timestamp":1790644349014,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009698","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000}}],"reference-count":102,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Theme-based Research scheme","award":["T12C-714\/14-R"],"award-info":[{"award-number":["T12C-714\/14-R"]}]},{"name":"Health Medical Research Fund","award":["HMRF 06171636"],"award-info":[{"award-number":["HMRF 06171636"]}]},{"DOI":"10.13039\/501100009480","name":"Stichting Vrienden van het Sophia","doi-asserted-by":"publisher","award":["S14-33"],"award-info":[{"award-number":["S14-33"]}],"id":[{"id":"10.13039\/501100009480","id-type":"DOI","asserted-by":"publisher"}]},{"name":"sophia foundation","award":["S14-33"],"award-info":[{"award-number":["S14-33"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                  <jats:p>\n                    This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without\n                    <jats:italic>RET<\/jats:italic>\n                    coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR\/Cas9 targeting confirmed the contribution of\n                    <jats:italic>UFD1L<\/jats:italic>\n                    ,\n                    <jats:italic>TBX2<\/jats:italic>\n                    ,\n                    <jats:italic>SLC8A1<\/jats:italic>\n                    , and\n                    <jats:italic>MAPK8<\/jats:italic>\n                    to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Rare large CN losses\u2014often\n                    <jats:italic>de novo<\/jats:italic>\n                    \u2014contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009698","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T13:35:38Z","timestamp":1628256938000},"page":"e1009698","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3330-1371","authenticated-orcid":true,"given":"Laura E.","family":"Kuil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9656-637X","authenticated-orcid":true,"given":"Katherine C.","family":"MacKenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0265-2638","authenticated-orcid":true,"given":"Clara S.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9300-0234","authenticated-orcid":true,"given":"Jonathan D.","family":"Windster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy Linh","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5795-6674","authenticated-orcid":true,"given":"Anwarul","family":"Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca M.","family":"de Graaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8050-9939","authenticated-orcid":true,"given":"Robert","family":"van der Helm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2002-9145","authenticated-orcid":true,"given":"Yolande","family":"van Bever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius E. J.","family":"Sloots","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conny","family":"Meeussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Tibboel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"de Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 M. H.","family":"Wijnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Amiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Lyonnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Merc\u00e8","family":"Garcia-Barcelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K. H.","family":"Tam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0083-5318","authenticated-orcid":true,"given":"Maria M.","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice S.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-3829","authenticated-orcid":true,"given":"Robert M. 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