Early onset or syndromic epilepsy

Gene: PHACTR1

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD EIEE 70. De Ligt et al, 2012 - 28 year old women - first developed seizures a 3 weeks of age - de novo het missense mutation. Hamada et al, 2018 - 2 unrelated Japanese children aged 4 and 5 - presented with seizures in first months of life - de novo het missense mutations, in vitro functional studies done.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy early infantile, 618298

Publications

• 30256902

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. At least 3 variants reported in unrelated cases, together with supportive functional studies (PMIDs: 23033978, 28135719), which support a dominant negative mode of action or incomplete penetrance.

Created: 27 Nov 2018, 1:26 p.m.

Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719)

Created: 27 Nov 2018, 1:25 p.m.

Green List (high evidence)

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).

At least 3 individuals appeared to have epilepsy (as this information is not available for the DDD participant).

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review

Created: 22 Nov 2018, 12:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

• 30256902
• 23033978
• 28135719