DPF2 was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2018 (Vasileiou et al., PMID: 29429572). DPF2-related Coffin-Siris syndrome is characterized by coarse facial features, global developmental delay/intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. Eleven de novo variants (missense, frameshift, large deletion and splice site) that have been reported in eleven probands in four publications (PMIDs: 29429572, 31207137, 31706665 and 35607970) are included in this curation. Functional assessment for three missense variants present in the critical PHD1 and PHD2 domains of DPF2 (p.Cys276Phe, p.Cys330Trp and p.Arg350His) demonstrate abolished or strongly reduced interaction with histone peptides, associated with loss of protein function. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. No experimental evidence currently supports this gene-disease relationship.
In summary, there is definitive evidence to support the relationship between DPF2 and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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