DPF2 – Coffin-Siris syndrome

DPF2 encodes a PHD finger–containing subunit of the BAF chromatin-remodeling complex, and heterozygous de novo variants in DPF2 have been implicated in Coffin-Siris syndrome (CSS), a multisystem neurodevelopmental disorder. Initial evidence from an eight-patient cohort demonstrated heterozygous de novo frameshift, splice, and missense variants clustering within PHD1 and PHD2 domains, all occurring in conserved zinc-coordination residues ([PMID:29429572]). Two independent case reports further support this association: one describes a novel de novo missense variant c.1066T>G (p.Cys356Gly) expanding features to include Pierre-Robin sequence and diaphragmatic hernia ([PMID:31207137]), and another reports a mild CSS phenotype in a patient with a distinct de novo DPF2 mutation identified by NGS ([PMID:31706665]).

CSS linked to DPF2 follows an autosomal dominant inheritance with all reported variants arising de novo and no evidence of familial segregation. Overall, ten unrelated probands (8 from cohort [PMID:29429572], 1 case report [PMID:31207137], 1 additional report [PMID:31706665]) exhibit overlapping clinical features, including hypoplastic toenails, coarse facial features, global developmental delay, intellectual disability, speech impairment, hypotonia, hypertrichosis, sparse scalp hair, and congenital diaphragmatic hernia.

Functional studies on DPF2 variants reveal impaired recognition of histone H3 tails: pull-down assays show loss or reduction of binding to unmodified and modified H3 peptides, while overexpression of mutant proteins in HEK293 and COS7 cells leads to nuclear aggregate formation and recruitment of wild-type DPF2 and BRG1, supporting a dominant-negative mechanism ([PMID:29429572]). Additional experimental data demonstrate DPF2’s role in OCT4 ubiquitination and nuclear distribution, implicating its importance in chromatin regulation during development ([PMID:26417682]).

An emerging link between CSS genes and congenital diaphragmatic hernia underscores phenotypic pleiotropy: DPF2, alongside other BAF complex genes, is now recognized among CSS-associated genes contributing to diaphragmatic development ([PMID:35796094]). No conflicting evidence has been reported to date.

Integration of genetic and functional data supports a strong gene-disease association for DPF2 and CSS. Key take-home: screening for de novo DPF2 variants should be included in diagnostic panels for neurodevelopmental disorders with CSS features and diaphragmatic anomalies.

References

• American journal of human genetics • 2018 • Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome. PMID:29429572
• American journal of medical genetics. Part A • 2019 • Expanding the phenotypic spectrum associated with DPF2: A new case report. PMID:31207137
• Brain & development • 2020 • A new missense mutation in DPF2 gene related to Coffin Siris syndrome 7: Description of a mild phenotype expanding DPF2-related clinical spectrum and differential diagnosis among similar syndromes epigenetically determined. PMID:31706665
• American journal of medical genetics. Part A • 2022 • Evidence for an association between Coffin-Siris syndrome and congenital diaphragmatic hernia. PMID:35796094

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