Early onset or syndromic epilepsy

Gene: TUBB2A

Green List (high evidence)

Associated with Cortical dysplasia, complex, with other brain malformations 5 in OMIM and G2P (confirmed).

PMID: 32571897 (2020) - 12 patients with eight novel and one recurrent variants in the TUBB2A gene. Phenotypic features included seizures (11/12), intellectual disability (12/12), speech impairment (12/12), severe motor developmental delay (11/12) with 4 patients being non-ambulatory.

A spectrum of brain malformations was reported in 11/12 participants, including tubulinopathy-related dysgyria of varying severity (7/12), abnormal corpus callosum (8/12), enlarged lateral ventricles (8/12), and dysmorphic basal ganglia (4/12). Four patients had mild hypoplasia of the cerebellar vermis and/or a dysmorphic vermis; the cerebellar hemispheres were hypoplastic in one patient. However, none exhibited any cerebellar signs or had any progressive cerebellar atrophy.

Created: 30 Jul 2020, 3:25 p.m. | Last Modified: 30 Jul 2020, 3:25 p.m.

Panel Version: 2.129

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cortical dysplasia, complex, with other brain malformations 5, 615763

Publications

• 32571897

Green List (high evidence)

AD DCBM5. Cushion et al, 2014 (24702957) - 2 unrelated children with a severe neurodevelopmental disorder - 1 child had seizures as part of phenotype, other child - milder especially regarding seizures observed (subtle vertical eye movements which resolved). 2 diff de novo het variants observed. In vitro functional expression studies in HEK293 cells showed that the N247K mutation prevented correct protein processing (more severly aff patient). The A248V mutant protein had a less severe effect, where it incorporated into the in vitro cytoskeleton network but more of the mutant protein remaining unpolymerised in the cytoplasm compared to wt. Lee et al, 2014 (25326637) - case 113 - seizures as part of phenotype had a novel de novo likely missense variant; case 107 - seizures as part of phenotype - de novo likely missense variant. Rodan et al, 2016 (27770045) - de novo previously reported missense variant - A248V (phenotype doesn't include seizures). Ejaz et al, 2017 (28840640) - seizures observed as part of phenotype - de novo missense variant R262H.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

Green List (high evidence)

OMIM phenotype #615763: CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5. 7 DM variants on HGMDPro, including epilepsy/spasm phenotype. PMID 24702957 reports two unrelated children with de novo missense variants (affecting adjacent codons, 247 and 248 which are reported to be in the GTP binding site). Functional studies show an effect on microtubule formation. One patient had infantile spasms at 5 months of age. EEG showed hypsarrhythmia and the other had hypotonia at 4 months of age; at 11 months an EEG showed frequent multifocal epileptiform discharges, and electrographic seizures characterized by brief bursts of diffuse spike and polyspike activity followed by amplitude attenuation.

Created: 23 Aug 2019, 10:01 a.m. | Last Modified: 23 Aug 2019, 10:01 a.m.

Panel Version: 1.256

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS

Publications

• 24702957

I don't know

AD complex cortical dysplasia, 2 unrelated cases reported on OMIM both had epilepsy - Cushion et al 2014.

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

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cortical dysplasia complex with other brain malformations 5, 615763

Publications

• 24702957

I don't know

Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway (West Midlands, Oxford and Wessex GLH).

Created: 7 Sep 2019, 10:30 a.m. | Last Modified: 7 Sep 2019, 10:30 a.m.

Panel Version: 1.267

Review and rating 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 that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

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

Panel Version: 1.262

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

Comment when marking as ready: Seizures are a reported phenotype of MIM:615763, with sufficient cases of seizures for inclusion on panel.

Created: 25 Sep 2018, 10:39 a.m.

Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain: 3 unrelated cases from literature (two cases from PMID:24702957 and one from large-scale study PMID:25326637. Although not all with the genotype may develop seizures, there are sufficient cases of the epilepsy phenotype for inclusion on the panel.

Created: 24 Sep 2018, 8:26 a.m. | Last Modified: 13 Aug 2019, 10:56 a.m.

Panel Version: 1.198

TUBB2A added to panel based on PMID:24702957 (2014), which describes two unrelated individuals with infantile-onset epilepsy and abnormalities of brain morphology harbouring de novo variants in TUBB2A. A third patient is reported in the large-scale study PMID:25326637 (2014); an infant with DD, seizures, perisylvian polymicrogyria and micropcephaly with a de novo missense variant in TUBB2A.
Sources: Literature

Created: 20 Sep 2018, 2:20 p.m.

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

Phenotypes
Cortical dysplasia, complex, with other brain malformations 5, 615763; infantile-onset epilepsy

Publications

• 24702957
• 25326637