Early onset or syndromic epilepsy

Gene: GTPBP2

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

Green List (high evidence)

AR Jaberi-Elahi syndrome (JABELS). Neurodev disorder characterised by dev delay and ID and additional features which can include seizures. Jaberi et al, 2016 - consang Iranian family - 4 adult sibs neurodev disorder -1/4 had generalised seizures - hom splice site variant identified segregated with disease in family. Bertoli-Avela et al 2013 - 3 unrelated children each born of consang parents with a severe neurodev syndrome. All had seizures - hom nonsense variants identified. No functional work done.

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
Jaberi-Elahi syndrome, 617988

Publications

• 26675814
• 29449720

Comment on phenotypes: added additional phenotype suggested by external reviewer

Created: 31 Oct 2018, 3:37 p.m.

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants homozygous variants identified in 4 unrelated cases whose phenotype included seizures.

Created: 26 Sep 2018, 8:43 a.m.

I don't know

PMID: 26675814 describes the phenotype of 3 sibs born to consanguineous parents. All presented with delayed early milestones and moderate intellectual disability (IQ 40-50). Cerebellar vermian atrophy was a feature noted in all. Movement anomalies, skeletal problems, abnormal vision and abnormalities of the skin and the hair were part of the phenotype. SWI MRI images were suggestive of brain iron accumulation. All 3 affected sibs shared a single homozygous region not found in homozygosity in their 2 unaffected sibs. Exome sequencing revealed a homozygous GTPBP2 splice variant within this region, leading to skipping of exon 9. The latter was confirmed by RT-PCR experiments. Presence of a truncated protein was confirmed following transfection of HEK293 cells. Mice homozygous for a splice variant were previously (PMID: 25061210) reported to present with similar features although it is not clear whether homozygosity for the GTPBP2 splice variant itself or presence of a concomitant mutation in a tRNA gene was responsible for all the features. //

PMID: 29449720 reports on 3 individuals born to consanguineous parents, all homozygous for GTPBP2 nonsense variants. These 3 individuals belonged to unrelated families. Common features included developmental delay and severe intellectual disability, seizures, visual impairment and skeletal anomalies. Brain MRI was suggestive of hypogenesis/agenesis of corpus callosum, brain atrophy with variable cerebellar hypoplasia. Hair, teeth or skin anomalies may be part of the phenotype. Compared to the previous article, MRI images were did not demonstrate hypointensities compatible with brain iron accumulation. //

DD/ID appears to be a universal feature while seizures have been reported in 4/6 individuals. As a result the gene can be considered for inclusion in the epilepsy panel as amber.

Created: 6 Sep 2018, 1:14 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

• 26675814
• 29449720
• 25061210