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Genetic epilepsy syndromes

Gene: D2HGDH

Green List (high evidence)

D2HGDH (D-2-hydroxyglutarate dehydrogenase)
EnsemblGeneIds (GRCh38): ENSG00000180902
EnsemblGeneIds (GRCh37): ENSG00000180902
OMIM: 609186, Gene2Phenotype
D2HGDH is in 10 panels

3 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

AR D-2 hydroxyglutaric aciduria - neurometabolic disorder characterised by dev delay, epilepsy, hypotonia and dysmorphic features. Severe pheno associated with EIEE, mild pheno - more variable. Struys et al, 2005 (incl patient from Gibson et al, 1993) - 2 unrelated patients - 1 hom for a missense variant, the other, compound het for missense and splice site, both patients were reported to have seizures. In addition another paper - 3 individuals from 2 unrelated pakistani families - hom variants detected. seizures reported in family 2 not family 1. Kranendijk et al, 2010 - identified presumed pathogenic variants in 24/50 patients with increased levels of D-2 hydroxyglutaric acid - no mention of clinical presentation.
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
D-2-hydroxyglutaric aciduria, 600721

Publications

Rebecca Foulger (Genomics England curator)

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. Green review, and as Zornitza reports, epilepsy is a phenotype of D-2-hydroxyglutaric aciduria. Sufficient unrelated epileptic cases from the literature (2 from PMID:15609246 and 1 from PMID:16037974) to support a diagnostic rating.
Created: 20 Nov 2018, 1:46 p.m.
Struys et al 2005 (PMID:15609246) report two unrelated patients affected with severe D-2-hydroxyglutaric aciduria and disease-causing variants in D2HGDH. Patient one suffered tonic, tonic-clonic, and myoclonic seizures, and was homozygous for missense variant in D2HGDH (c.1331T-->C; p.Val444Ala). Patient 2 presented with generalized tonic-clonic seizures and infantile spasms amongst her symptoms. She was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele.
Created: 20 Nov 2018, 1:42 p.m.
Struys et al. (2005, PMID:16037974) examined 3 patients from 2 unrelated consanguineous Palestinian families with mild D-2-hydroxyglutaric aciduria and homozygous variants in D2HGDH. In family 1, the two affected siblings were clinically asymptomatic and had the homozygous IVS4‐2A>G variant. Patient C (Family 2) is the only affected member of his family, and at age 8 years he developed absence seizures with myoclonic jerks amongst his symptoms. He had a Homozygous Asn439Asp variant in D2HGDH.
Created: 20 Nov 2018, 1:38 p.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Seizures are a common feature of this metabolic disorder.
Created: 12 Aug 2018, 6:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
D-2-hydroxyglutaric aciduria, MIM#600721

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • D-2-hydroxyglutaric aciduria, 600721
  • generalized tonic-clonic seizures
  • absence seizures
  • tonic seizures
  • tonic-clonic seizures
  • myoclonic seizures
OMIM
609186
Clinvar variants
Variants in D2HGDH
Penetrance
None
Panels with this gene

History Filter Activity

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to D2HGDH.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to D2HGDH.

11 Dec 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Seizures are a common feature

20 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: d2hgdh has been classified as Green List (High Evidence).

20 Nov 2018, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures, to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures

20 Nov 2018, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721 to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures,

20 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: d2hgdh has been classified as Green List (High Evidence).

20 Nov 2018, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: D2HGDH was changed from to BIALLELIC, autosomal or pseudoautosomal

20 Nov 2018, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria, 600721

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to D2HGDH. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

D2HGDH was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

D2HGDH was created by Sarah Leigh