Early onset or syndromic epilepsy

Gene: DOLK

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:59 a.m. | Last Modified: 11 Oct 2023, 11:59 a.m.

Panel Version: 4.110

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least five DOLK variants have been reported in four unrelated cases of Congenital disorder of glycosylation, type Im, OMIM:610768, where seizures were reported in the patients (PMID: 28816422 table 1)(PMID 24144945;23890587;17273964).

Created: 21 Feb 2023, 11:36 a.m. | Last Modified: 21 Feb 2023, 11:36 a.m.

Panel Version: 3.58

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 21 Feb 2023, 11:18 a.m. | Last Modified: 21 Feb 2023, 11:18 a.m.

Panel Version: 3.57

I don't know

Four families, one described in PMID 17273964, another in PMID 24144945 and the other two in PMID 23890587. Seizures were reported to be part of the congenital disorders of glycosylation phenotype in each family.

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 Im, 610768

Publications

• 23890587

I don't know

Please note the additional patients with seizures reported by Lieu et al. (PMID: 24144945) and Rush et al. (PMID: 28816422).

Created: 3 Dec 2018, 2:01 p.m.

Publications

• 24144945
• 28816422

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 insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.

Created: 25 Nov 2019, 8:48 p.m. | Last Modified: 25 Nov 2019, 8:48 p.m.

Panel Version: 1.438

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 on list classification: Updated rating from Amber to Green based on external review by Konstantinos Varvagiannis, the third case of seizures reported in PMID:24144945, and the review of seizure phenotypes also reported by PMID:24144945. Although seizures are not reported in all patients, the association of CDG is confirmed in DDG2P, seizures can be severe, and there are sufficient cases for inclusion on panel.

Created: 8 Jul 2019, 11:24 a.m. | Last Modified: 8 Jul 2019, 11:24 a.m.

Panel Version: 1.130

PMID:28816422 (Rush et al., 2017) report 2 sisters with novel compound het DOLK variants: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Patient 2 had one seizure at 53 days old- the seizures did not recur and the patient died age 64 days. Seizures were not noted for her sister (Patient 1), although she died at just over a week old.

Created: 8 Jul 2019, 11:18 a.m. | Last Modified: 8 Jul 2019, 11:18 a.m.

Panel Version: 1.128

PMID:24144945 (Lieu et al., 2013) report a male neonate born to non-consanguineous Palestinian origin parents, with phenotypes including dysmorphic features, genital abnormalities, talipes equinovarus, and severe refractory generalized seizures. He harboured a homozygous p.Q483K DOLK variant- in patient fibroblasts this missense variant severely reduced substrate binding and cataytic activity. They also summarise clinical data of previous DOLK-CDG patients, and report seizures in 7/18 patients (Table 1 and article text).

Created: 8 Jul 2019, 11 a.m. | Last Modified: 8 Jul 2019, 11 a.m.

Panel Version: 1.128

Added 'watchlist' tag.

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

Comment on list classification: Kept rating as Amber: 2 families reported so far (2 siblings from PMID:23890587 and 1 of 2 cousins in PMID:17273964). Zornitza confirmed (via email on Dec 1st 2018) that there's no further known cases.

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

Lebfer et al, 2011 (PMID:22242004) say epilepsy was not present in their patients with DOLK variants and dilated cardiomyopathy.

Created: 22 Nov 2018, 4:46 p.m.

PMID:17273964 (Kranz et al. 2007) report 2 affected first cousins in a consanguineous German family with homozygosity for a 295T-A transversion in the DOLK gene (C99S). For subject GH, seizures due to hypsarrhythmia started at age 7 wk. Subject NB, a first cousin of GH, had no seizures. The authors also report 2 Turkish siblings from consanguineous parents with a 1322A-C transversion in the DOLK gene (Y441S). No epilepsy was mentioned, although death occured age 7 mo and 4 mo.

Created: 22 Nov 2018, 4:42 p.m.

In 2 sibs, born of consanguineous Syrian Turkish parents with MIM:610768, Helander et al., 2013 (PMID:23890587) identified a homozygous c.2T-C transition in DOLK resulting in a change in the initiation methionine triplet. The patients presented at age 4 months with severe intractable seizures and hypsarrhythmia.

Created: 22 Nov 2018, 4:32 p.m.

Green List (high evidence)

Early presentation with seizures and demise reported in some individuals. Transferrin isoforms are not a reliable test in the newborn period to guide appropriate genomic analysis towards a CDG/metabolic panel; we also note the 25% recurrence risk, and hence we have included this gene as Green on our panel.

Created: 22 Jan 2020, 7:06 a.m. | Last Modified: 22 Jan 2020, 7:06 a.m.

Panel Version: 2.0

Seizures are a common feature of this metabolic disorder.

Created: 12 Aug 2018, 6:49 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital disorder of glycosylation, type Im, MIM#610768

Publications

• 23890587
• 28816422
• 24144945

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