Early onset or syndromic epilepsy
Gene: AKT1
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 AKT1 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, 10:23 a.m. | Last Modified: 15 Aug 2019, 10:23 a.m.
Panel Version: 1.233
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: Red. 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 Proteus syndrome. In addition somatic variants have been linked to Breast, colorectal, ovarian cancer and Cowden syndrome 6). Proteus syndrome - highly variable, severe disorder of asymmetric and disprop overgrowth of body parts. References used on panel app: Cohen, 2014 - review of molecular, clinical and pathological features - caused by an activating AKT1 mutation - Glu17Lys - seizures have been reported as a feature. If this is a somatic variant - surely we would have to test the affected tissue to detect the variant -? Include as may not be detectable in blood - Lindhurst et al, 2011 paper - only 2/38 peripheral blood samples collected from Proteus syndrome patients were positive for the mutation and that a molecualr diagnosis with the use of peripheral blood DNA may be challenging.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Phenotypes
Breast cancer, somatic, 114480; Colorectal cancer, somatic, 114500; Cowden syndrome, 615109; Ovarian cancer, somatic, 167000; Proteus syndrome, somatic 176920; {Schizophrenia, susceptibility to} 181500
Publications
Somatic mutations, multiple patients reported, seizures part of the phenotype. Recurrent mutation is activating.Created: 7 Aug 2018, 9:10 a.m.
Mode of inheritance
Other
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
Comment on mode of inheritance: Somatic mosaicismCreated: 27 Sep 2018, 9:04 a.m.
Comment on mode of pathogenicity: somatic mosaic activating variantsCreated: 26 Sep 2018, 2:58 p.m.
Comment on mode of inheritance: Somatic variantsCreated: 16 Jul 2018, 3:53 p.m.
Proteus syndrome is associated with mosaicism for a somatic activating mutation in the AKT1 gene. Epilepsy can be part of phenotypeCreated: 4 Jul 2018, 9:46 p.m.
Mode of inheritance
Other
Gene: akt1 has been classified as Red List (Low Evidence).
Gene: akt1 has been classified as Red List (Low Evidence).
Source Wessex and West Midlands GLH was added to AKT1.
Source NHS GMS was added to AKT1.
Arianna Tucci: Proteus syndrome is associated
Phenotypes for gene: AKT1 were changed from to Proteus syndrome, somatic 176920
Publications for gene: AKT1 were set to 23992099; 21793738
Mode of pathogenicity for gene: AKT1 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: AKT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: akt1 has been classified as Green List (High Evidence).
Mode of pathogenicity for gene: AKT1 was changed from None to None
Publications for gene: AKT1 were set to 23992099
Publications for gene: AKT1 were set to 23992099
Mode of inheritance for gene: AKT1 was changed from to Unknown
Expert Review Amber was added to AKT1. Panel: Genetic Epilepsy Syndromes
AKT1 was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
AKT1 was created by Sarah Leigh