Early onset or syndromic epilepsy

Gene: IDH2

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Refers to glioma patients- not a seizure disorder. Demoted from Green to RED.

Created: 25 Nov 2019, 8:54 p.m. | Last Modified: 26 Nov 2019, 4:10 p.m.

Panel Version: 1.475

A number of papers note that IDH1 and IDH2 variants have an established association with preoperative seizures in patients with grade II-IV diffuse gliomas (PMID:29172136, 29288860, 22217666).

Created: 21 Nov 2019, 2:44 p.m. | Last Modified: 21 Nov 2019, 2:44 p.m.

Panel Version: 1.417

PMID:24049096 (Nota et al., 2013) report 3 cases, with seizures reported in 2/3. Case 2 was a 9 year old Caucasian girl with tonic-clonic seizures and mosaic IDH2 variants. Case 3 was a Caucasian girl with seizures age 3 months- her seizures responded well to anticonvulsants. The patient died from sudden cardiac arrest age 8, and was found to have a heterozygous IDH2 c.419G>A variant. Germline mosaicism in the mother was suggested to explain the inheritance pattern in this family.

Created: 21 Nov 2019, 2:41 p.m. | Last Modified: 21 Nov 2019, 2:41 p.m.

Panel Version: 1.416

Comment on mode of inheritance: Kept Mode of Inheritance as MONOALLELIC based on post-Webex review from Helen Lord. Note that the rating of IDH2 was not discussed on the group Webex (2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy) because IDH2 has a Green rating on the 'Inborn errors of metabolism' panel, and therefore will be Green on the Epilepsy super panel for R59.

Created: 7 Sep 2019, 10:56 a.m. | Last Modified: 7 Sep 2019, 10:56 a.m.

Panel Version: 1.278

Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded an Amber rating to match the original West Midlands, Oxford and Wessex GLH rating.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Comment on mode of inheritance: The mode of inheritance for IDH2 is currently MONOALLELIC on the 'Intellectual disability' panel, and the 'Inborn errors of metabolism' panel.

Created: 13 Aug 2019, 12:59 p.m. | Last Modified: 13 Aug 2019, 12:59 p.m.

Panel Version: 1.206

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.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

I don't know

Cancer association. ?Consent. AD D-2-hydroxyglutaric acidurea 2 (D2HGA2) - Kranendijk et al, 2010 - phenotypically characterised 17 unrelated patients with D-2-hydroxyglutaric acidurea (phentype ranged from asymp to dev delay, epilepsy, hypotonia, cardiomyopathy and dysmoprhic features) who didn't have a mutation in the D2HGDH gene - 15/17 had mutations in the IH2 gene - 14 R140Q and 1 R140G, and arose de novo in 8/9 cases. In 1 family mother had 3 aff pregnancies and was shown to be a somatic mosaic. Functional studies have been done (2011).

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on mode of inheritance: Changed from 'other' to monoallelic, due to reports of heterozygous variants to enable variants in this gene to be tiered.

Created: 5 May 2017, 7:41 a.m.

Green List (high evidence)

Comment on mode of inheritance: >3 cases including PMID:20847235 who detected heterozygous germline variants in IDH2 that alter Arg140 in 15 unrelated patients with MIM:613657; in 14 cases the variant was de novo. The mother of 1 patient demonstrated germline mosaicism. PMID:24049096 also report a heterozygous IDH2 and the unaffected mother was a mosaic carrier. Somatic variants also reported.

Created: 20 Mar 2017, 12:19 p.m.

Inclusion of this as a green gene on this panel is appropriate, based on the review in the Undiagnosed metabolic disorders panel and the views of clinical expert, Dr Arianna Tucci, UCL.

Created: 20 Mar 2017, 12:18 p.m.

Mode of inheritance
Other

Phenotypes
D-2-hydroxyglutaric aciduria 2 613657

Publications

• 20847235