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

The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While <i>NIPBL</i> variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of <i>MAU2</i> in disease is unclear. We describe 18 individuals carrying 15 heterozygous <i>MAU2</i> variants and demonstrate pathogenicity through functional analyses. MAU2 in-frame variants predominantly impair NIPBL-MAU2 interaction, whereas truncating variants cause <i>MAU2</i> haploinsufficiency and lead to NIPBL reduction. Most patients exhibit a DNA methylation profile compatible with the CdLS episignature. We also identified two <i>MAU2</i>-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 <i>Mau2</i> knockout mouse model recapitulated these traits, confirming the causal role of <i>MAU2</i> disruption <i>in vivo</i>. Our study establishes <i>MAU2</i> as a new CdLS-associated gene and delineates a <i>MAU2</i>-related chromatinopathy with variable expressivity.