Intellectual disabilityGene: PHACTR1
Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719)
Created: 8 May 2019, 1:37 p.m.
Comment on list classification: 3 cases plus functional evidence (from PMIDs: 23033978, 28135719), supporting a dominant negative mode of action or incomplete penetrance.
Created: 8 May 2019, 1:33 p.m.
Associated with Epileptic encephalopathy, early infantile, 70 in OMIM and PHACTR1-associated neurodevelopment disorder in Gene2Phenotype (Probable).
PMID: 30256902 (Hamada et al., 2018) - 2 de novo heterozygous missense mutations [c.1449T > C/p.(Leu500Pro) and c.1436A > T/p.(Asn479Ile)] in PHACTR1, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability). Both showed epilepsy from 3 months of age and intellectual disability.
In vitro functional expression studies showed that these mutations interrupted actin binding, whereas R521C interrupted PP1 binding. Functional studies in mice show that the two variants found here and the two from previous studies were unable to rescue the neuronal migration defects in Phactr1-null mice, suggesting that they are pathogenic. Expression of the mutations in mice induced migration defects and caused abnormal cortical architecture in a dominant-negative manner.
In PMID: 28135719 (McRae et al 2017) - in Supplementary Table 1 there are two individuals recruited with a severe undiagnosed developmental disorder and with missense variants in PHACTR1, one is validated. Both individuals have variants in other genes.
PMID: 23033978 (de Ligt et al., 2012) - 1 patient with severe intellectual disability had missense variant in PHACTR1 c.1561C>T p.(Arg521Cys). Hamada et al 2018 note that this variant is found in four out of 123 080 individuals on the Genome Aggregation Database (gnomAD) database (= 0.003%).
PMID: 27457812 (Riazuddin et al., 2017) - 1 patient with intellectual disability from consanguineous parents with candidate missense variants in CPT1B and PHACTR1 (Table 3b)
Created: 14 Feb 2019, 10:50 p.m.
PMID: 30256902 (Hamada et al., 2018) reports on the phenotype of 2 unrelated individuals with de novo missense variants in PHACTR1. Both had a diagnosis of West syndrome (infantile spasms and intellectual disability).
As the authors note, 3 individuals with missense variants in this gene (in 2 of whom as a de novo occurrence) were previously identified :
- In PMID: 23033978 (de Ligt et al., 2012) one patient with ID and epilepsy and a de novo missense variant.
- In PMID: 28135719 (DDD study in 2017) one individual with developmental disorder and a further de novo missense SNV.
- PMID: 27457812 (Riazuddin et al., 2017) is an exome sequencing study for intellectual disability. (NB. In the supplement of this study, the consanguineous parents of the affected individuals appear to be heterozygous for this variant but the affected children non-carriers).
Extensive functional studies for the 2 novel as the 2 previously reported variants (from PMIDs: 23033978, 28135719) support a dominant negative effect for all 4 variants.
One of these variants (reported by de Ligt al.) for which pathogenicity is suggested has however been reported 4 times in gnomAD. The authors discuss the possibility of reduced penetrance and/or other phenotypes in the individuals from gnomAD.
Although all the variants studied appear to have a dominant negative effect, Phactr1-knockdown neurons seem to display aberrant migration and morphological phenotype. As a result, the eventual effect of haploinsufficiency probably needs to be further clarified. (Still PHACTR1 has a pLI score of 0.66 in ExAC).
As a result, this gene can be considered for upgrade to green (or amber).
Created: 22 Nov 2018, 12:19 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Global developmental delay; Intellectual disability; Seizures
There is currently no evidence to suggest there is an association of this gene with intellectual disability.
Created: 18 Dec 2017, 3:39 p.m.
Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder
Phenotypes for gene: PHACTR1 were changed from to Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder
Publications for gene: PHACTR1 were set to
Mode of pathogenicity for gene: PHACTR1 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
Mode of inheritance for gene: PHACTR1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: phactr1 has been classified as Green List (High Evidence).
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
PHACTR1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
PHACTR1 was created by ellenmcdonagh