Pathogenic variants in the cohesin loader subunit MAU2 lead to a new Cornelia de Lange Syndrome subtype

Abstract 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. MAU2 in-frame variants predominantly impair NIPBL–MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. Most patients exhibit a DNA methylation profile compatible with the CdLS episignature. We also identified 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 consistent features. A heterozygous Mau2 knockout mouse model recapitulated these traits, confirming the causal role of MAU2 disruption in vivo. Our study establishes MAU2 as a new CdLS-associated gene and delineates a MAU2-related chromatinopathy with variable expressivity. Competing Interest Statement A.A.L.J. reported receiving consulting fees and grants from BioMarin, Novo Nordisk and BridgeBio. S.E.A. is a co-founder and CEO of Medigenome, Swiss Institute of Genomic Medicine. All other authors declare no conflict of interest. Funding Statement I.P. is supported by the CHOPS Rare Disease Foundation, and F.J.K. receives support from the Dr. Holger Mueller Stiftung. S.C.C. is a Senior Lecturer at the University Bourgogne-Europe. B.Y. is an INSERM investigator supported by grants from the Agence Nationale de la Recherche and the IFCPAR/CEFIPRA (grant no. 6503-J). A.A.L.J. is supported by the Sao Paulo Research Foundation (FAPESP; 2022/10107-6), and the National Council for Scientific and Technological Development (CNPq; 303294/2020-5). F.J.R., J.P., B.P. and M.G.S. are investigators supported by grants from the Instituto de Salud Carlos III (Grant Ref. PI23-01370) and Diputacion General de Aragon-FEDER: European Social Fund [Reference Group B32_20R]. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was approved by the Ethic Committee of the University Hospital Essen (UME-ID-12571). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript