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

Ilaria Parenti; Alina Hesters; Marta Gil‐Salvador; Laura Duffy; Deniz Kanber; Jasmin Beygo; Jennifer Kerkhof; Laura Steenpaß; Elsa Leitão; Julia Woestefeld; Philip M. Boone; Emeline M. Kao; Lama AlAbdi; Hesham Aldhalaan; Fowzan Sami Alkuraya; Muneera J. Alshammari; Stylianos E. Antonarakis; Donald Basel; Kévin Cassinari; Laurana de Polli Cellin; Amanda R. Clause; Alexander A.L. Jorge; Andréa de Castro Leal; Stephan C. Collins; Benjamin Durand; Juliane Eckhold; Mais Hashem; Parul Jayakar; Arif O. Khan; Kohji Kato

doi:10.1038/s41467-026-71177-6

Genetic & Genomic MedicineNature CommunicationsMar 30, 2026

Peer-reviewed journal article

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

Ilaria Parenti iD, Alina Hesters iD, Marta Gil‐Salvador iD, Laura Duffy iD, Deniz Kanber iD, Jasmin Beygo iD, Jennifer Kerkhof iD, Laura Steenpaß iD, Elsa Leitão iD, Julia Woestefeld iD, Philip M. Boone iD, Emeline M. Kao, Lama AlAbdi iD, Hesham Aldhalaan iD, Fowzan Sami Alkuraya iD, Muneera J. Alshammari, Stylianos E. Antonarakis iD, Donald Basel iD, Kévin Cassinari iD, Laurana de Polli Cellin iD, Amanda R. Clause iD, Alexander A.L. Jorge iD, Andréa de Castro Leal iD, Stephan C. Collins iD, Benjamin Durand iD, , Frank J. Kaiser

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.

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