Early onset or syndromic epilepsy

Gene: TRIM8

Green List (high evidence)

AD Epileptic encepalopathy - paper by Assoum et al, AJMG, 2018. 6 unrelated patients discussed in total with TRIM8 variants - fs/nonesense variants - all de novo and clustered close together in the C-terminal.

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
epileptic encephalopathy

Publications

• 27346735
• 30244534

I don't know

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: Green.

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

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green based on recent publication: 6 unrelated cases of patients with EE and TRIM8 variants reviewed by the recent PMID:30244534 (includes the two cases previously reported cases in PMID:27346735 and PMID:23934111 plus 4 new cases). Therefore sufficient evidence to support inclusion on diagnostic panel.

Created: 3 Nov 2018, 11:29 a.m.

Green List (high evidence)

PMID: 30244534 is a collaborative study reporting on the phenotype of TRIM8-related epileptic encephalopathy and summarizing the findings in previously published patients. Developmental delay, intellectual disability, seizures are common findings in the 6 unrelated individuals reported. Proteinuria was observed in 3 subjects.

Seizures were universal feature with highly variable age of onset (2 months to 3 years and 5 months).

Several individuals were investigated for developmental delay prior to seizure onset (eg. pat.1 had an MRI at 10 months, sat at 16 months, walked at 22 months and developed seizures at 2 years, pat.3 sat at 12 months, walked at 22 and developed seizures at 3 years and 5 months, pat. 4 and 5 had significant/severe delay prior to the age of 21 months when they started having seizures).

All variants reported to date are truncating, affecting the last (sixth exon) and as a result may escape nonsense-mediated decay. Since TRIM8 homodimerizes via its (upstream) coiled-coil domain and its C-terminal domain is required for nuclear localization, a dominant-negative effect is postulated by the authors. Haploinsufficiency appears less likely.

A previously reported patient (from PMID: 27346735) as well as an individual reported by the Epi4K consortium (PMID: 23934111 - among the co-authors of the present study) are included in the table of this article.

As a result this gene can be upgraded to green.

Created: 17 Oct 2018, 2:38 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

• 30244534
• 27346735
• 23934111

Green List (high evidence)

Please note new publication reporting 4 additional patients presenting with EE and de novo truncating mutations of TRIM8.

Created: 23 Oct 2018, 6 a.m.

Single family reported to date.

Created: 22 Aug 2018, 6:54 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
EE

Publications

• 27346735, 30244534

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