Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders.
Nat Genet
; 55(8): 1400-1412, 2023 08.
Article
de En
| MEDLINE
| ID: mdl-37500730
ABSTRACT
DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Assemblage et désassemblage de la chromatine
/
Troubles du développement neurologique
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Nat Genet
Sujet du journal:
GENETICA MEDICA
Année:
2023
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique