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Early onset or syndromic epilepsy v2.372 | PHACTR1 | Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures to Developmental and epileptic encephalopathy 70, OMIM:618298 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.191 | PHACTR1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to PHACTR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.190 | PHACTR1 | Rebecca Foulger Source NHS GMS was added to PHACTR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.189 | PHACTR1 | Rebecca Foulger reviewed gene: PHACTR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.188 | PHACTR1 | Tracy Lester reviewed gene: PHACTR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30256902; Phenotypes: Epileptic encephalopathy early infantile, 618298; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1175 | PHACTR1 | Sarah Leigh Marked gene: PHACTR1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1175 | PHACTR1 | Sarah Leigh Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1175 | PHACTR1 | Sarah Leigh Gene: phactr1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1175 | PHACTR1 | Sarah Leigh Added comment: Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1175 | PHACTR1 | Sarah Leigh Mode of pathogenicity for gene: PHACTR1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1174 | PHACTR1 | Sarah Leigh Classified gene: PHACTR1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1174 | PHACTR1 | Sarah Leigh Gene: phactr1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1060 | PHACTR1 |
Konstantinos Varvagiannis gene: PHACTR1 was added gene: PHACTR1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: PHACTR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PHACTR1 were set to 30256902; 23033978; 28135719 Phenotypes for gene: PHACTR1 were set to Global developmental delay; Intellectual disability; Seizures Penetrance for gene: PHACTR1 were set to unknown Review for gene: PHACTR1 was set to GREEN Added comment: 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 |