{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:01:54Z","timestamp":1753869714416,"version":"3.41.2"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In addition to patient\u2010related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%\u201350% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the <jats:italic>RET<\/jats:italic> proto\u2010oncogene. We thus hypothesized that <jats:italic>RET<\/jats:italic> variants contribute to the etiology of AP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNA from paraffin\u2010embedded appendices and clinical data of 264 children were analyzed for the <jats:italic>RET c<\/jats:italic>.<jats:italic>135A<\/jats:italic>&gt;<jats:italic>G<\/jats:italic> variant (rs1800858, NC_000010.11:g.43100520A&gt;G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for <jats:italic>RET<\/jats:italic> sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Germline mutations were found in 13% of GAP, whereas no <jats:italic>RET<\/jats:italic> mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A&gt;T). In GAP, the polymorphic G\u2010allele in rs2435352 (NC_000010.11:g.43105241A&gt;G) in intron 4 was underrepresented (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0317).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest an impact of the <jats:italic>RET<\/jats:italic> proto\u2010oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including <jats:italic>RET<\/jats:italic> germline mutations with phenotypic heterogeneity and incomplete penetrance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1864","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T06:39:48Z","timestamp":1641278388000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distribution of <i>RET<\/i> proto\u2010oncogene variants in children with appendicitis"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5638-8663","authenticated-orcid":false,"given":"Jurek","family":"Schultz","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Freibothe","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Haase","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Glatte","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo","family":"Barreton","sequence":"additional","affiliation":[{"name":"Institute of Pathology University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Medizincampus Davos  Davos Switzerland"},{"name":"School of Mathematics Statistics and Computer Science  Pietermaritzburg South Africa"},{"name":"University Heart Center Hamburg University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"G\u00f6rgens","sequence":"additional","affiliation":[{"name":"Department of Surgical Research University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Fitze","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery University of Technology Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a115734"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.053959"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-012-1749-z"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-006-0056-y"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/302329"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jhered.a104359"},{"issue":"2","key":"e_1_2_10_8_1","first-page":"377","article-title":"Inheritance of acute appendictis: Familial aggregation and evidence of polygenic transmission","volume":"46","author":"Basta M.","year":"1990","journal-title":"American Journal of Human Genetics"},{"issue":"3","key":"e_1_2_10_9_1","first-page":"770","article-title":"A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A 1","volume":"83","author":"Berndt I.","year":"1998","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"issue":"3","key":"e_1_2_10_10_1","first-page":"770","article-title":"A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia Type 2A","volume":"83","author":"Berndt I.","year":"1998","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00275-5"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.268"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.36.10.771"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-07-0817"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2338"},{"key":"e_1_2_10_16_1","first-page":"590","article-title":"Appendectomy in Australian twins","volume":"47","author":"Duffy D. L.","year":"1990","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03467"},{"volume-title":"GeneReviews\u00ae [Internet]","year":"1993","author":"Eng C.","key":"e_1_2_10_18_1"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/145749690709600405"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg354"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2003-41270"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08218-1"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9161"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1086\/302618"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1053\/jpsu.2001.25765"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jso.25371"},{"issue":"8","key":"e_1_2_10_27_1","first-page":"e5322","article-title":"The characteristics of appendicoliths associated with acute appendicitis","volume":"11","author":"Khan M. S.","year":"2019","journal-title":"Cureus"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bjsopen\/zraa045"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03353-0"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.4149\/BLL_2015_138"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2010.02.039"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2018.07.071"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-015-0235-5"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.137.3.529"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2363"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/dgd.12664"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00423-013-1139-5"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1375\/twin.12.2.150"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-018-1956-2"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.sla.0000133184.10676.26"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2009.09.039"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-011-1150-7"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.6736"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1997)9:3<243::AID-HUMU5>3.0.CO;2-8"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2010.00577.x"},{"key":"e_1_2_10_46_1","doi-asserted-by":"crossref","unstructured":"Sim\u00f3 Alari F. Gutierrez I. &Gimen\u00e9z P\u00e9rez J.(2017). Familial history aggregation on acute appendicitis.BMJ Case Reports 2017 bcr\u20102016\u2010218838. https:\/\/doi.org\/https:\/\/doi.org\/10.1136\/bcr\u20102016\u2010218838","DOI":"10.1136\/bcr-2016-218838"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.2214\/AJR.18.21019"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-14-0491"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1355"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1089\/1050725041692990"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-193910000-00011"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-016-9446-3"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2009.02137.x"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101294"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1864","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1864","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1864","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T04:04:44Z","timestamp":1693109084000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1864"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1002\/mgg3.1864"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1864","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2022,1,3]]},"assertion":[{"value":"2021-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1864"}}