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Genetic epilepsy syndromes

Gene: DOLK

Amber List (moderate evidence)

DOLK (dolichol kinase)
EnsemblGeneIds (GRCh38): ENSG00000175283
EnsemblGeneIds (GRCh37): ENSG00000175283
OMIM: 610746, Gene2Phenotype
DOLK is in 14 panels

4 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

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

Konstantinos Varvagiannis (Other)

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

Rebecca Foulger (Genomics England curator)

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.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

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

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

History Filter Activity

25 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: dolk has been classified as Amber List (Moderate Evidence).

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to DOLK.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to DOLK.

8 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: dolk has been classified as Green List (High Evidence).

8 Jul 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: DOLK were set to 23890587; 17273964

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Seizures are a common feature

3 Dec 2018, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: dolk has been classified as Amber List (Moderate Evidence).

3 Dec 2018, Gel status: 2

Added Tag

Rebecca Foulger (Genomics England curator)

Tag watchlist tag was added to gene: DOLK.

3 Dec 2018, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: dolk has been classified as Amber List (Moderate Evidence).

22 Nov 2018, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: DOLK were set to 23890587

22 Nov 2018, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: DOLK were set to

22 Nov 2018, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: DOLK was changed from to BIALLELIC, autosomal or pseudoautosomal

22 Nov 2018, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: DOLK were changed from to Congenital disorder of glycosylation, type Im, 610768

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to DOLK. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

DOLK was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

DOLK was created by Sarah Leigh