{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T10:27:23Z","timestamp":1784975243511,"version":"3.55.0"},"posted":{"date-parts":[[2025,11,22]]},"group-title":"Genetic and Genomic Medicine","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While\n                  <jats:italic>NIPBL<\/jats:italic>\n                  variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of\n                  <jats:italic>MAU2<\/jats:italic>\n                  in disease is unclear. We describe 18 individuals carrying 15 heterozygous\n                  <jats:italic>MAU2<\/jats:italic>\n                  variants and demonstrate pathogenicity through functional analyses. MAU2 in-frame variants predominantly impair NIPBL\u2013MAU2 interaction, whereas truncating variants cause\n                  <jats:italic>MAU2<\/jats:italic>\n                  haploinsufficiency and lead to NIPBL reduction. Most patients exhibit a DNA methylation profile compatible with the CdLS episignature. We also identified two\n                  <jats:italic>MAU2<\/jats:italic>\n                  -specific episignatures that reflect variant-dependent molecular consequences. Affected individuals display a wide range of phenotypes, from classic CdLS to milder presentations, with short stature and microcephaly as consistent features. A heterozygous\n                  <jats:italic>Mau2<\/jats:italic>\n                  knockout mouse model recapitulated these traits, confirming the causal role of\n                  <jats:italic>MAU2<\/jats:italic>\n                  disruption\n                  <jats:italic>in vivo.<\/jats:italic>\n                  Our study establishes\n                  <jats:italic>MAU2<\/jats:italic>\n                  as a new CdLS-associated gene and delineates a\n                  <jats:italic>MAU2<\/jats:italic>\n                  -related chromatinopathy with variable expressivity.\n                <\/jats:p>","DOI":"10.1101\/2025.11.16.25339042","type":"posted-content","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T17:20:14Z","timestamp":1763832014000},"source":"Crossref","is-referenced-by-count":1,"title":["Pathogenic variants in the cohesin loader subunit MAU2 lead to a new Cornelia de Lange Syndrome 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