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

Abstract

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

Expanding the phenotypic spectrum associated with DPF2: A new case report

“…Subsequent to our finding, eight individuals with CSS were reported harboring de novo variants in DPF2 (MIM: 618027) (Vasileiou et al, ). Patient variants significantly reduced binding to posttranslationally modified H3 tails and formed nuclear protein aggregates composed of both wild‐type and mutant forms of DPF2, indicating a dominant‐negative pathogenic mechanism (Vasileiou et al, ).…”

“…Subsequent to our finding, eight individuals with CSS were reported harboring de novo variants in DPF2 (MIM: 618027) (Vasileiou et al, ). Patient variants significantly reduced binding to posttranslationally modified H3 tails and formed nuclear protein aggregates composed of both wild‐type and mutant forms of DPF2, indicating a dominant‐negative pathogenic mechanism (Vasileiou et al, ). In common with our variant, several of the variants described in Vasileiou et al () were missense changes altering cysteine (such as Cys276, Cys330) or other residues required to coordinate the Zn 2+ atoms within the PHD domains (Huber et al, ).…”

“…Sequencing efforts have established CSS as a disorder of chromatin‐remodeling, specifically caused by disruption of the BAF complex—a 12–28 subunit ATP‐dependent chromatin‐remodeling complex, required for multiple essential roles during early organism development (Ho & Crabtree, ). Recently, pathogenic de novo missense or truncating variants in DPF2 , a member of the BAF complex, were described in eight individuals with CSS (Vasileiou et al, ). While the characteristic features of CSS were present amongst the DPF2 mutation‐positive cohort, there were less common CSS features such as craniosynostosis and hearing loss present at a higher frequency among the DPF2 cohort.…”

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

“…8,25 Recently, mutations identified in BAF-subunit DPF2 were suggested to cause CSS-like phenotype in a dominant-negative mechanism related both to missense and splicing/truncating variants through NMD escape. 17 Given that SMARCC1 and SMARCC2 are paralogous genes, that they can form heterodimers or homodimers, 70 and that both share functional scaffolding properties, 28 it is conceivable that SMARCC1 could at least partially compensate for the loss of SMARCC2 leading to a milder phenotype in case subjects with truncating mutations in the SMARCC N-terminal region. Nevertheless, our results also suggest that the mutant mRNA of individual 4 (c.1311À3C>G) undergoes NMD as one of the consequences of the splice site mutation, thereby indicating that haploinsufficiency can also be seen in individuals with a severe phenotype.…”

“…ATPase subunit SMARCA4 (MIM: 603254), the common core subunit SMARCB1 (MIM: 601607), and BAF accessory subunits such as SMARCE1/BAF57 (MIM: 603111), ARID1A (MIM: 603024), ARID1B (MIM: 614556), 15 ARID2 (MIM: 609539), 16 and DPF2 (MIM: 601671). 17 CSS can result of pathogenic changes in other chromatin remodeling proteins with no direct interaction with BAF complex, including SOX11 (MIM: 600898) 18 and PHF6 (MIM: 300414). 19 Other BAFopathies include Nicolaides-Baraitser syndrome (MIM: 601358) caused by pathogenic variants in SMARCA2 (MIM: 600014) that has a significant phenotypic overlap with CSS and is characterized by ID, sparse hair, short stature, microcephaly, brachydactyly, interphalangeal joint swellings, and epilepsy.…”