170395 20260420103354.0 doi 10.1038/s41467-026-71177-6 sideral 148866 ART-2026-148866 eng Parenti, Ilaria Pathogenic variants in the cohesin loader subunit MAU2 underlie a distinct Cornelia de Lange Syndrome subtype 2026 The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While NIPBL variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of MAU2 in disease is unclear. We describe 18 individuals carrying 15 heterozygous MAU2 variants and demonstrate pathogenicity through functional analyses. In-frame MAU2 variants predominantly impair NIPBL–MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. Most individuals exhibit a DNA methylation profile compatible with the CdLS episignature. We also describe two MAU2-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 major features. A heterozygous Mau2 knockout mouse model recapitulates these traits, confirming the causal role of MAU2 disruption in vivo. Our study establishes MAU2 as a CdLS-associated gene and delineates a MAU2-related chromatinopathy with variable expressivity. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/DGA-FEDER/B32-20R info:eu-repo/grantAgreement/ES/ISCIII/PI23-01370 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Hesters, Alina Gil-Salvador, Marta (orcid)0000-0001-6858-1575 Duffy, Laura Kanber, Deniz Beygo, Jasmin Kerkhof, Jennifer Steenpaß, Laura Leitão, Elsa Woestefeld, Julia Boone, Philip M. Kao, Emeline M. Alabdi, Lama Aldhalaan, Hesham M. Alkuraya, Fowzan S. Alshammari, Muneera J. Antonarakis, Stylianos E. Basel, Donald Cassinari, Kevin de Polli Cellin, Laurana Clause, Amanda R. de Lima Jorge, Alexander Augusto de Castro Leal, Andréa Collins, Stephan C. Durand, Benjamin Eckhold, Juliane Hashem, Mais O. Jayakar, Parul Khan, Arif O. Kato, Kohji Kubica, Regina Lyon, Gholson J. Marchi, Elaine McCarrier, Julie Kimmig, Lara K. Mizuno, Seiji Nicolas, Gael Nishio, Yosuke Ogi, Tomoo Pié, Juan Prell, Jordyn Puisac, Beatriz Ramos, Feliciano J. Universidad de Zaragoza (orcid)0000-0002-5732-2209 Ranza, Emmanuelle Redin, Claire Rush, Eric Saitoh, Shinji Shamseldin, Hanan E. Starling, Susan Astiazaran-Symonds, Esteban Eltahir, Sara H. Kuechler, Alma Sadikovic, Bekim Yalcin, Binnaz Wendt, Kerstin S. Kaiser, Frank J. 1011 670 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Pediatría 17, 1 (2026) Nature communications 2041-1723 6809155 http://zaguan.unizar.es/record/170395/files/texto_completo.pdf Versión publicada 2781652 http://zaguan.unizar.es/record/170395/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:170395 articulos driver 2026-04-18-10:48:45 ARTICLE