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Intellectual disability

Gene: DPF2

Green List (high evidence)

DPF2 (double PHD fingers 2)
EnsemblGeneIds (GRCh38): ENSG00000133884
EnsemblGeneIds (GRCh37): ENSG00000133884
OMIM: 601671, Gene2Phenotype
DPF2 is in 3 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.

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

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

Caroline Wright (Sanger)

Red List (low evidence)

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

Lu Raymond (university of cambridge )

Red List (low evidence)

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

History Filter Activity

9 Aug 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: dpf2 has been classified as Green List (High Evidence).

9 Aug 2018, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: DPF2 were set to Coffin-Siris syndrome 7, 618027; intellectual disability

9 Aug 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: DPF2 were set to 26350204; 29429572

9 Aug 2018, Gel status: 1

Set mode of pathogenicity

Louise Daugherty (Genomics England Curator)

Mode of pathogenicity for gene: DPF2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

9 Aug 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: DPF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

9 Aug 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: DPF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

9 Aug 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: DPF2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene DPF2 was set to ['26350204']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

DPF2 was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

DPF2 was created by ellenmcdonagh