{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:33:39Z","timestamp":1772559219853,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,28]]},"group-title":"Genetic and Genomic Medicine","reference-count":109,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"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":[[2026,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cohesin is a fundamental genome-organizing complex that orchestrates three-dimensional chromosome folding and gene expression via DNA loop extrusion. Alterations to genes encoding cohesin subunits and cohesin loaders cause Mendelian disorders, including Cornelia de Lange syndrome (CdLS). By contrast, disruption of factors that remove cohesin from DNA, including\n                  <jats:italic>WAPL<\/jats:italic>\n                  and its binding partners\n                  <jats:italic>PDS5A<\/jats:italic>\n                  and\n                  <jats:italic>PDS5B<\/jats:italic>\n                  , have not yet been associated with human disease. Here, we explored the relevance of these cohesin release factors in Mendelian disease by establishing a rare disease cohort of deeply phenotyped individuals with heterozygous, predicted damaging variants in\n                  <jats:italic>WAPL<\/jats:italic>\n                  (n=27),\n                  <jats:italic>PDS5A<\/jats:italic>\n                  (n=8), and\n                  <jats:italic>PDS5B<\/jats:italic>\n                  (n=8), by modeling\n                  <jats:italic>WAPL<\/jats:italic>\n                  deficiency in human cell lines and mice, and by aggregating rare disease association statistics from consortia studies. We identified a\n                  <jats:italic>WAPL<\/jats:italic>\n                  -related disorder characterized by developmental delay, intellectual disability, and risk of other developmental anomalies including clubfoot. Similarities between individuals with damaging\n                  <jats:italic>WAPL<\/jats:italic>\n                  variants and those with large, recurrent 10q22.3q23.2 (10q) deletions (which encompass\n                  <jats:italic>WAPL<\/jats:italic>\n                  ) nominate\n                  <jats:italic>WAPL<\/jats:italic>\n                  as a driver gene within this genomic disorder region. While carriers of\n                  <jats:italic>PDS5A<\/jats:italic>\n                  or\n                  <jats:italic>PDS5B<\/jats:italic>\n                  variants exhibited features of developmental disorders, neither cohort-based statistics nor case phenotyping associated these genes with specific phenotypes. We used CRISPR engineering to generate truncating variants in\n                  <jats:italic>WAPL<\/jats:italic>\n                  , as well the 7.8 Mb 10q deletion or duplication in human iPSCs and induced neurons. Transcriptomic analyses identified differentially expressed genes in both models, with highly significant overlap between\n                  <jats:italic>WAPL<\/jats:italic>\n                  haploinsufficiency and 10q deletion signatures. Mice with 50% residual\n                  <jats:italic>Wapl<\/jats:italic>\n                  expression exhibited mild deficits of growth and learning\/memory, whereas those with 25% residual\n                  <jats:italic>Wapl<\/jats:italic>\n                  expression displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. In summary, we delineated a novel genetic condition caused by cohesin release factor deficiency, nominated\n                  <jats:italic>WAPL<\/jats:italic>\n                  as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin.\n                <\/jats:p>","DOI":"10.64898\/2026.02.23.26346364","type":"posted-content","created":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T01:05:31Z","timestamp":1772327131000},"source":"Crossref","is-referenced-by-count":0,"title":["Clinical,\n                  <i>in vitro,<\/i>\n                  and\n                  <i>in vivo<\/i>\n                  evidence of\n                  <i>WAPL<\/i>\n                  as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"],"prefix":"10.64898","author":[{"given":"Philip M.","family":"Boone","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA, US"},{"name":"Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children\u2019s Hospital, Boston, MA, US"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, US,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serkan","family":"Erdin","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, US,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abucar","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Section on Epigenetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadegheh","family":"Haghshenas","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, LHSC, London, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamli N. W.","family":"Faour","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emeline","family":"Kao","sequence":"additional","affiliation":[{"name":"Institutional Centers for Clinical and Translational Research, Boston Children\u2019s Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack","family":"Fu","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Auwerx","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, US,"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Harripaul","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bimal","family":"Jana","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Springer","sequence":"additional","affiliation":[{"name":"Murine Phenotyping Core Facility, National Heart Lung and Blood Institute, Bethesda, MD, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grey","family":"Hallstrom","sequence":"additional","affiliation":[{"name":"Epigenetics Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celine E.F.","family":"de Esch","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica","family":"Denhoff","sequence":"additional","affiliation":[{"name":"Institutional Centers for Clinical and Translational Research, Boston Children\u2019s Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Holmes","sequence":"additional","affiliation":[{"name":"Institutional Centers for Clinical and Translational Research, Boston Children\u2019s Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiana","family":"Mohajeri","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Lemanski","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, LHSC, London, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haley","family":"McConkey","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, LHSC, London, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Rzasa","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, LHSC, London, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison J.","family":"McCune","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael 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F.","family":"Andersen","sequence":"additional","affiliation":[{"name":"ARUP Laboratories, Salt Lake City, UT, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela","family":"Argilli","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, CA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee","family":"Araiza","sequence":"additional","affiliation":[{"name":"Mutant Mouse Resource and Research Center, University of California, Davis, CA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Ballal","sequence":"additional","affiliation":[{"name":"Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children\u2019s Hospital, Boston, MA, US"},{"name":"Division of Gastroenterology, Boston Children\u2019s Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan F.","family":"Baxter","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK"},{"name":"Guy\u2019s and St Thomas\u2019 Hospital, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaber","family":"Bergant","sequence":"additional","affiliation":[{"name":"Clinical Institute for Genomic Medicine, UMC Ljubljana, Ljubljana, SI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Bertsche","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology and Inherited Metabolic Diseases, University Medicine Greifswald, Greifswald, DE"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riya","family":"Bhavsar","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debora 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Malformatifs, Centre de r\u00e9f\u00e9rence D\u00e9ficiences Intellectuelles de Causes Rares, et Centre de r\u00e9f\u00e9rence G\u00e9noPsy, FHU TRANSLAD, Equipe GAD INSERM UMR1231, Universit\u00e9 Bourgogne Europe, CHU Dijon Bourgogne, Inserm, Dijon, FR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8986-8222","authenticated-orcid":false,"given":"Anne-Sophie","family":"Denomm\u00e9-Pichon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CHU Dijon Bourgogne, Laboratoire de G\u00e9nomique M\u00e9dicale, Centre Neomics, FHU-TRANSLAD, Centre de recherche Translationnelle en M\u00e9decine mol\u00e9culaire \u2013 Inserm UMR1231, \u00e9quipe GAD, Dijon, FR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koenraad","family":"Devriendt","sequence":"additional","affiliation":[{"name":"UZ Leuven, Leuven, 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