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Intellectual disability
Gene: PCGF2

PCGF2 (polycomb group ring finger 2)
EnsemblGeneIds (GRCh38): ENSG00000277258
EnsemblGeneIds (GRCh37): ENSG00000056661
OMIM: 600346, Gene2Phenotype
PCGF2 is in 3 panels

5 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Turnpenny et al. (https://doi.org/10.1016/j.ajhg.2018.09.012) report on 13 individuals (11 unrelated and a pair of monozygotic twins) all with missense PCGF2 mutations affecting a specific residue (proline 65).

The unrelated individuals were found to harbor the p.(Pro65Leu) [NM_007144.2:c.194C>T] mutation as a de novo event, while the twins had a different mutation at the same residue [p.(Pro65Ser) or c.193C>T] which was inherited from their mosaic unaffected mother (21% in her blood DNA).

Common features include developmental delay, intellectual disability, impaired growth as well as a distinct facial phenotype. There was variable cerebral, cardiovascular (aortic dilatation in 5 individuals) as well as skeletal involvement.

The authors suggest a dominant negative effect rather than haploinsufficiency. gnomAD has several truncating PCGF2 variants (pLI score of 0.55). The authors comment that there are no interstitial deletions involving the gene in DECIPHER.

As a result this gene can be re-upgraded to Green.
Created: 18 Oct 2018, 10:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system

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: 18 Oct 2018, 10:30 p.m.

Panel version: 2.510

Louise Daugherty (Genomics England Curator)

Green List (high evidence)

Comment on publications: Added PMID: 30343942 to support upgrading of this gene to green
Created: 31 Oct 2018, 1:29 p.m.

Comment on phenotypes: added phenotype suggested by external reviewer/ from PMID:30343942
Created: 31 Oct 2018, 1:23 p.m.

Comment on list classification: Recent publication suggested by external reviewer PMID: 30343942 supports the rating of this gene to be Green
Created: 31 Oct 2018, 1:15 p.m.

removed watchlist tag
Created: 31 Oct 2018, 1:12 p.m.

Added watchlist tag.
Created: 9 Oct 2018, 2:39 p.m.

Comment on list classification: Downgraded gene from Green to Amber after considering Red external clinical review and additional internal clinical review
Created: 7 Aug 2018, 3:46 p.m.

After internal clinical review it was recommended to downgrade gene from Green to Amber. There are three cases in decipher with a specific missense variant and varying features that include global delay / specific learning disability, these are conceivably appropriate phenotypes, however further information on this and the mechanism of the variant / mutational spectrum within the gene are required before consider rating as Green
Created: 7 Aug 2018, 3:42 p.m.

Comment on list classification: changed back to Green until clinical team review to confirm downgrading gene
Created: 30 Jul 2018, 11:33 a.m.

Referred to internal clinical team or for further review
Created: 30 Jul 2018, 11:31 a.m.

Comment on list classification: Changed Green to Amber due to external expert review and lack of publications since 2015 to support gene-disease association for variants of PCGF2 and ID
Created: 30 Jul 2018, 11:30 a.m.

Comment on phenotypes: Added phenotype from PMID: 25533962 (Intellectual disability; dysmorphic features). The authors noted that the patients had a strikingly similar facial appearance
Created: 30 Jul 2018, 11:21 a.m.

Comment on publications: added Decipher publications
Created: 30 Jul 2018, 11:19 a.m.

The Deciphering Developmental Disorders Study (2015) identified 2 unrelated patients with intellectual disability who shared the same heterozygous missense mutation in the PCGF2 gene https://www.ebi.ac.uk/gene2phenotype/gfd?search_type=gfd&dbID=1057. However, there is no additional supportive evidence in recent publications to associate this gene to intellectual disability and there is also no functional studies of the variant performed to warrant this gene being green. Agree with recent external reviewer comment that this gene needs to be downgraded from Green.
Created: 30 Jul 2018, 11:18 a.m.

Created: 30 Jul 2018, 11:18 a.m.

Panel version: 2.531

Zornitza Stark (Australian Genomics)

Red List (low evidence)

Can't find published evidence
Created: 20 Jun 2018, 9:46 a.m.

Created: 20 Jun 2018, 9:44 a.m.

Panel version: 2.104

Caroline Wright (Sanger)

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
INTELLECTUAL DUSBILITY

Publications

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

Panel version: 0

Lu Raymond (university of cambridge )

Green List (high evidence)

Created: 23 Feb 2016, 10:54 a.m.

Panel version: 0.306

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green

Phenotypes

Intellectual disability
dysmorphic features
Global developmental delay
Abnormality of the cardiovascular system
Abnormality of the cerebrum
Abnormality of the skeletal system

OMIM

600346

Clinvar variants

Variants in PCGF2

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