Intellectual disability
Gene: DPF2

DPF2 (double PHD fingers 2)
EnsemblGeneIds (GRCh38): ENSG00000133884
EnsemblGeneIds (GRCh37): ENSG00000133884
OMIM: 601671, Gene2Phenotype
DPF2 is in 4 panels

5 reviews

Louise Daugherty (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Changed from Red to Green, there is now enough evidence to support the intellectual disability phenotype
Created: 9 Aug 2018, 8:17 a.m.

Comment on publications: Added publication suggested from external expert review to support upgrading of the gene to Green
Created: 9 Aug 2018, 8:15 a.m.

Comment on mode of pathogenicity from expert review. Appears to be dominant negative effects from missense mutations rather than LOF. ref: Vasileiou et al., (2018) PMID: 29429572 "Despite the intolerance to loss-of function variants (as evidenced by the high pLI value), haploinsufficiency seems unlikely given that the annotation of deletions encomprassing DPF2 in normal populations indicates that a complete loss of one allele could be neutral. On the contrary,the clustering of all variants within an evolutionarily highly concerved region, as previously described for other BAF subunits (SMARCA4, SMARCA2, SMARCB1, and SMARCE1), the nuclear aggregation phenotype, and the recruitment of wild-type DPF2 and BRG1 to the aggregates indicate a dominant negative effect.
Created: 9 Aug 2018, 8:14 a.m.

added dominant-negative tag
Created: 9 Aug 2018, 8:12 a.m.

Comment on mode of inheritance: added MO suggested by expert review and publication
Created: 9 Aug 2018, 8:11 a.m.

New review added by external expert who notes that there are now 8 unrelated individuals reported by Vasileiou et al., (2018) PMID: 29429572 with features of Coffin-Siris syndrome, ID is part of the phenotype. The publication supports gene-disease association and rating of this gene to Green.
Created: 9 Aug 2018, 8:06 a.m.

Created: 9 Aug 2018, 8:06 a.m.

Panel version: 2.319

Rachel Jones (GSTT)

Green List (high evidence)

PMID: 29429572 reports DPF2 as a new Coffin-Siris gene. The protein interacts with other subunits of the BAF complex.

They reported de novo mutations in DPF2 [OMIM: 601671], "encoding a subunit of the BAF chromatin-remodelling complex, which has not previously been associated with neurodevelopmental syndromes. In total, we identified eight unrelated individuals (four females and four males) with features of Coffin-Siris syndrome"

Functional and computational evidence was also provided to support pathogenicity:
"In summary, the following lines of evidence support the pathogenicity of the identified DPF2 variants: (1) their de novo occurrence, (2) the PHD finger mutational hotspot, (3) the intolerance of DPF2 and especially its encoded tandem PHD finger domain to variation, and (4) the fact that functional analyses of the missense alterations showed abolished or attenuated H3 binding and the formation of nuclear DPF2 aggregates."

Appears to be dominant negative effects from missense mutations rather than LOF
"Despite the intolerance to loss-of function variants (as evidenced by the high pLI value),
haploinsufficiency seems unlikely given that the annotation of deletions encomprassing DPF2 in normal populations indicates that a complete loss of one allele could be neutral. On the contrary,the clustering of all variants within an evolutionarily highly concerved region, as previously described for other BAF subunits (SMARCA4, SMARCA2, SMARCB1, and SMARCE1), the nuclear aggregation phenotype, and the recruitment of wild-type DPF2 and BRG1 to the aggregates indicate a dominant negative effect."
Created: 8 Aug 2018, 1:43 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Coffin-Siris syndrome 7 618027

Publications

PMID: 29429572

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 8 Aug 2018, 1:43 p.m.

Panel version: 2.308

Caroline Wright (Sanger)

Red List (low evidence)

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Ellen McDonagh (Genomics England Curator)

Red List (low evidence)

Not related to a disease in OMIM or Gene2Phenotype. Not evidence found related to clinical ID cases in literature search. Candidate gene for ID in PMID 26350204.
Created: 27 Oct 2017, 2:46 p.m.

Publications

26350204

Created: 27 Oct 2017, 2:46 p.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.2

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:34 a.m.

Panel version: 0.306

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green

Phenotypes

Coffin-Siris syndrome 7, 618027
intellectual disability

Tags

dominant-negative

OMIM

601671

Clinvar variants

Variants in DPF2

Penetrance

Complete

Publications

Mode of Pathogenicity

Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Panels with this gene