Early onset or syndromic epilepsy

Gene: AKT1

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 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

Red List (low evidence)

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

• 25722288

Green List (high evidence)

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

• 21793738

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Somatic mosaicism

Created: 27 Sep 2018, 9:04 a.m.

Comment on mode of pathogenicity: somatic mosaic activating variants

Created: 26 Sep 2018, 2:58 p.m.

Comment on mode of inheritance: Somatic variants

Created: 16 Jul 2018, 3:53 p.m.

Green List (high evidence)

Proteus syndrome is associated with mosaicism for a somatic activating mutation in the AKT1 gene. Epilepsy can be part of phenotype

Created: 4 Jul 2018, 9:46 p.m.

Mode of inheritance
Other