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Genetic epilepsy syndromes

Gene: PIK3CA

Red List (low evidence)

PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
EnsemblGeneIds (GRCh38): ENSG00000121879
EnsemblGeneIds (GRCh37): ENSG00000121879
OMIM: 171834, Gene2Phenotype
PIK3CA is in 21 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

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

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

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 Conway et al, 2007 - Longitudinal study of 17 unpublished patients (neuroimaging findings) - genetic cause still unknown 5/17 had seizures.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

Eleanor Williams (Genomics England Curator)

Comment when marking as ready: Sufficient cases
Created: 22 Nov 2018, 11:12 a.m.
Comment on list classification: > 3 cases of variants in this gene associated with phenotype, and with seizures
Created: 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 mosiacism
Created: 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.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Wessex and West Midlands GLH
  • NHS GMS
  • Victorian Clinical Genetics Services
Phenotypes
  • Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic 602501
Tags
mosaicism somatic
OMIM
171834
Clinvar variants
Variants in PIK3CA
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

15 Aug 2019, Gel status: 1

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: pik3ca has been classified as Red List (Low Evidence).

15 Aug 2019, Gel status: 1

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: pik3ca has been classified as Red List (Low Evidence).

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to PIK3CA.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to PIK3CA.

11 Dec 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Monoallelic, somatic. Seizures

22 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: pik3ca has been classified as Green List (High Evidence).

22 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: pik3ca has been classified as Green List (High Evidence).

22 Nov 2018, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: PIK3CA were changed from to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic 602501

22 Nov 2018, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: PIK3CA were set to

22 Nov 2018, Gel status: 2

Set mode of pathogenicity

Eleanor Williams (Genomics England Curator)

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

21 Nov 2018, Gel status: 2

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: PIK3CA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

21 Nov 2018, Gel status: 2

Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag mosaicism tag was added to gene: PIK3CA. Tag somatic tag was added to gene: PIK3CA.

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to PIK3CA. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

PIK3CA was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

PIK3CA was created by Sarah Leigh