Intellectual disability
Gene: DPF2
Comment on list classification: Changed from Red to Green, there is now enough evidence to support the intellectual disability phenotypeCreated: 9 Aug 2018, 8:17 a.m.
Comment on publications: Added publication suggested from external expert review to support upgrading of the gene to GreenCreated: 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 tagCreated: 9 Aug 2018, 8:12 a.m.
Comment on mode of inheritance: added MO suggested by expert review and publicationCreated: 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.
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
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
Gene: dpf2 has been classified as Green List (High Evidence).
Phenotypes for gene: DPF2 were set to Coffin-Siris syndrome 7, 618027; intellectual disability
Publications for gene: DPF2 were set to 26350204; 29429572
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
Mode of inheritance for gene: DPF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: DPF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: DPF2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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.
Publications for gene DPF2 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
DPF2 was added to Intellectual disabilitypanel. Sources: Expert Review Red
DPF2 was created by ellenmcdonagh