Early onset or syndromic epilepsy
Gene: PIK3CA
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote PIK3CA from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.Created: 15 Aug 2019, 10:25 a.m. | Last Modified: 15 Aug 2019, 10:25 a.m.
Panel Version: 1.235
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: Amber. Technical notes: PI3K/AKT pathway mutations can cause a spectrum of brain malformations that lead to seizures; however, these are likely to be somatic mutations. Would WGS be appropriate for this pathway for peripheral blood?.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
PI3K/AKT pathway mutations can cause a spectrum of brain malformations that lead to seizures, however, these are likely to be somatic mutations. Would WGS be appropriate for this pathway for peripheral blood? Somatic megalencephaly-capillary malformation-polymicrogyria syndrome. Spectrum of anomalies. Lapunzina et al, 2004 - out of 75 patients summarised 8/75 had seizures - paper is pre the gene being identified. Conway et al, 2007 - Longitudinal study of 17 unpublished patients (neuroimaging findings) - genetic cause still unknown 5/17 had seizures. Lee et al, 2012 - de novo somatic variants identifed - i think these were detectable in tissue but not in blood sample. Riviere et al, 2012 - 24/37 patients with identifiable PIK3CA variants with megalencephaly - de novo in 20 of these. Variants were detected in blood - tends to be at lower levels in blood than other tissues.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Comment when marking as ready: Sufficient casesCreated: 22 Nov 2018, 11:12 a.m.
Comment on list classification: > 3 cases of variants in this gene associated with phenotype, and with seizuresCreated: 22 Nov 2018, 11:11 a.m.
Comment on mode of pathogenicity: Gain of function (Gene2Phenotype)Created: 22 Nov 2018, 11:03 a.m.
Comment on mode of inheritance: Note somatic mosiacismCreated: 21 Nov 2018, 3:02 p.m.
Associated with Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic in OMIM and Gene2Phenotype (confirmed, activating mutations).
Riviere et al. (2012)(PMID: 22729224) 15 mostly postzygotic mutations of PIK3CA in 23 MCAP and one MPPH patient. 1 patient (LR09-006) is reported to have seizures in a previous paper (Mirzaa et al 2012 (PMID: 22228622). Mirzaa et al report that 16/42 patients they examined had seizures although one had febrile seizures only, variants were not looked at.
Lee et al. (2012)(PMID: 22729223) report 4 Hemimegalencephaly patients with the same de novo somatic mutation c.1633G>A, pGlu545Lys in PIK3CA. All had seizures (Supplementary Table 1). Individuals with HME were identified through the UCLA Pediatric Epilepsy Surgery Program database and although the ethnic background of the patients wasn't given it is unlikely that this is a founder effect. The PIK3CA p.Glu545Lys variation is thought to constitutively activate the mTOR pathway.Created: 21 Nov 2018, 2:57 p.m.
Monoallelic, somatic. Seizures are part of the phenotype.Created: 19 Aug 2018, 11:07 a.m.
Mode of inheritance
Other
Phenotypes
Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501
Variants in this GENE are reported as part of current diagnostic practice
Gene: pik3ca has been classified as Red List (Low Evidence).
Gene: pik3ca has been classified as Red List (Low Evidence).
Source Wessex and West Midlands GLH was added to PIK3CA.
Source NHS GMS was added to PIK3CA.
Zornitza Stark: Monoallelic, somatic. Seizures
Gene: pik3ca has been classified as Green List (High Evidence).
Gene: pik3ca has been classified as Green List (High Evidence).
Phenotypes for gene: PIK3CA were changed from to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic 602501
Publications for gene: PIK3CA were set to
Mode of pathogenicity for gene: PIK3CA 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
Mode of inheritance for gene: PIK3CA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Tag mosaicism tag was added to gene: PIK3CA. Tag somatic tag was added to gene: PIK3CA.
Expert Review Amber was added to PIK3CA. Panel: Genetic Epilepsy Syndromes
PIK3CA was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
PIK3CA was created by Sarah Leigh