Early onset or syndromic epilepsy

Gene: ALG8

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 enough evidence to rate this gene Green. Although there is inconsistency amongst patients, there are sufficient cases for a Green rating. Kept rating as Green.

Created: 25 Nov 2019, 8:30 p.m. | Last Modified: 25 Nov 2019, 8:30 p.m.

Panel Version: 1.431

PMID:19688606 (Vesela et al., 2009) present a girl with neonatal onset of CDG. Seizures were present from the first day and the girl died age 2 months from progressive oedema, bleeding and cardio-respiratory insufficiency. She had compound het variants in ALG8 (p.T47P and p.R364X).

Created: 21 Nov 2019, 9:49 p.m. | Last Modified: 21 Nov 2019, 9:49 p.m.

Panel Version: 1.425

PMID:23430830 (Millon et al., 2011) report 2 siblings with a congenital glycosylation disorder. Their clinical presentation included seizures. The authors could not identify the genetic deficiency in these patients yet.

Created: 21 Nov 2019, 9:46 p.m. | Last Modified: 21 Nov 2019, 9:46 p.m.

Panel Version: 1.425

26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) was seen in 12/13 patients.

Created: 21 Nov 2019, 9:46 p.m. | Last Modified: 22 Nov 2019, 9:25 a.m.

Panel Version: 1.425

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 congenital disorder of glycosylation type Ih - majority of patients have brain involvement, liver pathology, gastrointestinal symptoms, dysmorphism, eye involvement and skin symptoms. Chantret et al, 2003, Schollen et al 2004 - no mention of seizures/epilepsy. Not listed as feature on OMIM. HGMD Pro - Vesela et al, 2009 - girl born at 29 weeks - multifocal myoclonic seizures - compund het for a missense and a nonsense variant. Eklund et al, 2004 - patient presented with seizures hom missense variant. Bastaki et al, 2017 - 10 patients from 8 families - patient 4 had infantile spasms, patient 5 had epilepsy, but her younger brother patient 6 doesn't, patient 7 uncontrollable seizures, patient 8 - epilepsy. None of the patients with seizures had ALG8 variants.

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
Congenital disorder of glycosylation, type Ih 608104; Polycystic liver disease 3 with or without kidney cysts 617874

Green List (high evidence)

Seizures described in these publications as part of the phenotype.

Created: 7 Aug 2018, 9:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 26066342, 23430830, 19688606

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

Associated with Congenital disorder of glycosylation, type Ih 608104 in OMIM and as confirmed Gen2Phen, however, neither resource recorded seizures among the phenotypic features. Variants have been reported in at least 13 cases carrying biallelic ALG8 variants PMIDs 26066342 & 19688606.

Created: 12 Nov 2018, 11:30 a.m.

Comment on list classification: Based on evidence in publications 26066342 & 19688606

Created: 12 Nov 2018, 11:14 a.m.

Comment on list classification: Based on review by Arianna Tucci (Genomics England Curator)

Created: 16 Jul 2018, 3:16 p.m.

Red List (low evidence)

epilepsy has not been described in Congenital disorder of glycosylation type Ih

Created: 4 Jul 2018, 10:09 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal