Early onset or syndromic epilepsy

Gene: TUBA8

I don't know

Four cases from two consanguinous families had features including developmental delay and seizures- the same variant was identified in both families (PMID 19896110)

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

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical dysplasia complex with other brain malformations 8, 613180

Publications

• 19896110

I don't know

Comment on list classification: Kept rating as Amber for now, following Zornitza Stark's recent (Jan 2020) review. Additional case in PMID:31481326 (2020) but 2 Pakistani families (4 patients) previously reported may be related so remains a borderline case.

Created: 26 May 2020, 3:12 p.m. | Last Modified: 26 May 2020, 3:12 p.m.

Panel Version: 2.63

Reviewing 2020 review comment by Zornitza noting additional publication: PMID:31481326. PMID:31481326. Lee et al., 2020 used targeted gene sequencing to identify malformations of cortical development in 81 patients. A homozygous TUBA8 p.Asn356ProfsTer63 variant was identified in one patient with 'Polymicrogyria, agenesis of CC, ventriculomegaly'. All patients had a confirmed diagnosis of epilepsy or DD.

Created: 26 May 2020, 3:10 p.m. | Last Modified: 26 May 2020, 3:10 p.m.

Panel Version: 2.62

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: Alison Callaway and John Taylor. 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: Amber rating appropriate until further TUBA8 cases are confirmed. Added 'watchlist' tag.

Created: 3 Nov 2018, 10:32 a.m.

Comment on list classification: Kept rating as Amber. The phenotype is appropriate for the panel as seizures are part of MIM:613180, but insufficient cases for diagnostic rating. TUBA8 is a confirmed DD-G2P gene for 'POLYMICROGYRIA WITH OPTIC NERVE HYPOPLASIA' (the former name for Cortical dysplasia, complex, with other brain malformations 8, 613180), and TUBA8 is on the UKGTN 43 gene panel for brain malformations. HOWEVER, the 4 literature cases (with all 4 patients showing seizures) come from 2 consanguineous families reported in one 2009 paper (PMID:19896110), and at least PMID:25008804 questions whether the families are related.

Leeds, Oxford (Usha Kini) and Cardiff genetic testing labs all confirmed (personal communication via email) that they have not seen any TUBA8 cases for their cortical malformations panel.

Based on this evidence, Helen Brittain, Clinical Fellow agreed on Amber rating for TUBA8.

Created: 3 Nov 2018, 10:30 a.m.

Fung et al (PMID:29588952, 2017) selected a cohort of 31 patients with seizure cryptogenic NIEE (neonatal/infantile epileptic encephalopathy). A compound heterozygous variant of uncertain significance was found in TUBA8 in a patient with severe ID, developmental regression, hypotonia and seizures. Unlike in the 2009 paper (PMID:19896110), no malformation of cortical development was seen.

Created: 24 Sep 2018, 3:46 p.m.

4 patients with 'Cortical dysplasia, complex, with other brain malformations 8, MIM:613180' were reported by Abdollahi et al. (2009, PMID:19896110). The 4 children come from 2 consanguineous Pakistani families, and all 4 children presented with seizures (infantile spasms or Tonic clonic). In both families, affected individuals harbour a homozygous 14bp deletion in TUBA8. Although the families were not knowingly related, at least PMID:25008804 questions if the families were indeed related.

Created: 24 Sep 2018, 2:59 p.m.

Comment on mode of inheritance: Biallelic MOI supported by G2P, OMIM and literature (PMID:19896110).

Created: 24 Sep 2018, 2:57 p.m.

I don't know

Another affected individual reported as part of a bigger brain malformations cohort.

Created: 25 Jan 2020, 9:59 a.m. | Last Modified: 25 Jan 2020, 9:59 a.m.

Panel Version: 2.0

I can only find two reported families. Seizures are part of the phenotype in this brain development disorder.

Created: 22 Aug 2018, 7:24 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical dysplasia, complex, with other brain malformations 8, MIM#613180

Publications

• 31481326

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