{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T13:59:35Z","timestamp":1774447175365,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,23]]},"group-title":"Gastroenterology","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mowat Wilson syndrome (MWS) is a rare neurodevelopmental disorder caused by mostly heterozygous loss-of-function variants in\n                  <jats:italic>ZEB2<\/jats:italic>\n                  . Affected individuals show considerable wide variability in clinical presentation. In particular, Hirschsprung disease (HSCR) occurs in only a subset of patients, suggesting that additional genetic factors may modify disease penetrance. To investigate this possibility, we performed whole-genome sequencing of two parent-child trios in which the probands carried pathogenic\n                  <jats:italic>de novo ZEB2<\/jats:italic>\n                  variants but differed in enteric phenotype: one individual with MWS and long-segment HSCR and another with MWS without HSCR. In both probands, the\n                  <jats:italic>ZEB2<\/jats:italic>\n                  variants represent the primary causative genomic diagnosis, and no additional rare coding variants or excess copy-number burden provided a clear alternative explanation for HSCR. Phasing of a previously defined 10 single nucleotide polymorphisms(SNPs)\n                  <jats:italic>RET<\/jats:italic>\n                  enhancer haplotype revealed inheritance of a high-risk haplotype in the proband with HSCR, whereas the proband without HSCR carried only low-risk haplotypes on both chromosomes. To place these findings in a developmental context, we analysed single-cell transcriptomic data from the developing human fetal gut and neocortex.\n                  <jats:italic>ZEB2<\/jats:italic>\n                  and\n                  <jats:italic>RET<\/jats:italic>\n                  show overlapping expression in enteric neural crest progenitors and neuroblasts but minimal overlap in the developing neocortex, indicating that reduced\n                  <jats:italic>RET<\/jats:italic>\n                  dosage is likely to have tissue-specific effects in the enteric nervous system. Together, these results support a model in which common regulatory variation at\n                  <jats:italic>RET<\/jats:italic>\n                  modifies HSCR penetrance in the setting of\n                  <jats:italic>ZEB2<\/jats:italic>\n                  haploinsufficiency. More broadly, our findings illustrate how whole-genome sequencing can reveal regulatory modifiers that contribute to variable expressivity in ostensibly monogenic disorders\n                <\/jats:p>","DOI":"10.64898\/2026.03.19.26348831","type":"posted-content","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T18:15:19Z","timestamp":1774289719000},"source":"Crossref","is-referenced-by-count":0,"title":["Whole Genome Sequencing Reveals a\n                  <i>RET<\/i>\n                  Enhancer Risk Haplotype Associated with Hirschsprung Disease in Mowat Wilson Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8070-4939","authenticated-orcid":false,"given":"Sydney","family":"Collins","sequence":"first","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8941-4539","authenticated-orcid":false,"given":"Ibrahim","family":"Bah","sequence":"additional","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Pysar","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, UNSW Medicine and Health, Randwick Clinical Campus, Discipline of Pediatrics, University of New South Wales, Sydney, NSW, Australia"},{"name":"Centre for Clinical Genetics, Sydney Children\u2019s Hospital, Randwick, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mowat","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, UNSW Medicine and Health, Randwick Clinical Campus, Discipline of Pediatrics, University of New South Wales, Sydney, NSW, Australia"},{"name":"Centre for Clinical Genetics, Sydney Children\u2019s Hospital, Randwick, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-6477","authenticated-orcid":false,"given":"Tychele N.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-1698","authenticated-orcid":false,"given":"Sumantra","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Center for Human Genetics & Genomics, New York University Grossman School of Medicine New York, NY 10016, USA"},{"name":"Department of Neuroscience and Physiology, New York University Grossman School of Medicine New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026032505150691000_2026.03.19.26348831v1.1","first-page":"568","article-title":"A genetic study of Hirschsprung disease","volume":"46","year":"1990","journal-title":"Am J Hum Genet"},{"key":"2026032505150691000_2026.03.19.26348831v1.2","doi-asserted-by":"crossref","unstructured":"Birkhoff JC , Huylebroeck D , Conidi A . 2021. 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