Intellectual disability - microarray and sequencing
Gene: PCGF2
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
Comment on publications: Added PMID: 30343942 to support upgrading of this gene to greenCreated: 31 Oct 2018, 1:29 p.m.
Comment on phenotypes: added phenotype suggested by external reviewer/ from PMID:30343942Created: 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 GreenCreated: 31 Oct 2018, 1:15 p.m.
removed watchlist tagCreated: 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 reviewCreated: 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 GreenCreated: 7 Aug 2018, 3:42 p.m.
Comment on list classification: changed back to Green until clinical team review to confirm downgrading geneCreated: 30 Jul 2018, 11:33 a.m.
Referred to internal clinical team or for further reviewCreated: 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 IDCreated: 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 appearanceCreated: 30 Jul 2018, 11:21 a.m.
Comment on publications: added Decipher publicationsCreated: 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=10571057. 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.
Can't find published evidenceCreated: 20 Jun 2018, 9:46 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
INTELLECTUAL DUSBILITY
Publications
Mode of pathogenicity for gene: PCGF2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Publications for gene: PCGF2 were set to 25529582; 25533962
Phenotypes for gene: PCGF2 were changed from Intellectual disability; dysmorphic features; Global developmental delay; Intellectual disability; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system to Intellectual disability; dysmorphic features; Global developmental delay; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system
Phenotypes for gene: PCGF2 were changed from Intellectual disability; dysmorphic features to Intellectual disability; dysmorphic features; Global developmental delay; Intellectual disability; Abnormality of the cardiovascular system; Abnormality of the cerebrum; Abnormality of the skeletal system
Gene: pcgf2 has been classified as Green List (High Evidence).
Tag watchlist was removed from gene: PCGF2.
Tag watchlist tag was added to gene: PCGF2.
Gene: pcgf2 has been classified as Amber List (Moderate Evidence).
Gene: pcgf2 has been classified as Green List (High Evidence).
Gene: pcgf2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: PCGF2 were set to Intellectual disability; dysmorphic features
Publications for gene: PCGF2 were set to 25529582; 25533962
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.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
PCGF2 was added to Intellectual disabilitypanel. Sources: Expert Review Green
PCGF2 was created by ellenmcdonagh