Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Chromatin Biology

Background:

• Variants in the BAF chromatin-remodeling complex cause neurodevelopmental syndromes like Coffin-Siris syndrome.
• Proteins with PHD fingers, which recognize histone modifications, are linked to neurological and developmental disorders.

Purpose of the Study:

• To investigate the role of de novo variants in the DPF2 gene in Coffin-Siris syndrome.
• To elucidate the molecular mechanisms underlying DPF2-associated pathogenicity.

Main Methods:

• Identification and characterization of eight heterozygous de novo variants in DPF2.
• Analysis of clinical features in affected individuals.
• In vitro pull-down assays to assess DPF2-histone binding.
• Cellular studies involving overexpression of DPF2 variants and analysis of nuclear aggregates.
• Nonsense-mediated decay analysis of aberrant transcripts.

Main Results:

• Eight de novo DPF2 variants (1 frameshift, 2 splice site, 5 missense) were identified in individuals with Coffin-Siris syndrome features.
• Variants affect conserved PHD finger motifs, disrupting DPF2 binding to histone tails and potentially impairing histone modification recognition.
• Overexpression of DPF2 variants leads to nuclear aggregate formation and recruitment of wild-type DPF2 and BRG1.
• Aberrant transcripts from truncating variants escape nonsense-mediated decay.

Conclusions:

• De novo variants in DPF2 are a cause of Coffin-Siris syndrome.
• Pathogenicity likely involves a dominant-negative mechanism through disruption of DPF2 function and formation of nuclear aggregates.