Mitochondrial disorders

Gene: OGDH

Green List (high evidence)

Comment on list classification: There are five unrelated families reported with biallelic OGDH variants and functional evidence available in support of the association. OGDH is part of a multicomplex enzyme involved in the Kreb cycle and this gene is associated with mitochondrial disease with 'Definitive' rating by Mitochondrial Diseases GCEP in ClinGen.

However, expert review has been requested from NHSE as the recommendation for promotion to green rating has previously been disagreed by the NHSE suggesting that this gene is not associated with primary mitochondrial disease.

Created: 29 Jul 2026, 7:39 p.m. | Last Modified: 29 Jul 2026, 7:39 p.m.

Panel Version: 10.18

Oxoglutarate dehydrogenase, also known as alpha-ketoglutarate dehydrogenase or E1k (EC: 1.2.4.2) is one of the three subunits of the multienzyme alpha-ketoglutarate (alpha-KG) dehydrogenase complex, while other two subunits are dihydrolipoyl succinyltransferase (DLST or E2k) and dihydrolipoyl dehydrogenase (DLD or E3). This complex catalyzes a key reaction in the Krebs tricarboxylic acid cycle that takes place inside the mitochondrial matrix.

There are six patients from five families reported with four different homozygous variants in OGDH gene and with a neurodevelopmental disorder with metabolic and movement abnormalities. Age of onset of the disease ranged from 6 weeks of age to 3 years old. All described individuals shared the clinical features of global developmental delay, hypotonia, metabolic acidosis and increased serum lactate. Additional shared clinical features included dystonia (5/6), microcephaly (3/4), abnormal nasal bridge morphology (3/6), hyperammonemia (3/6), hyperglutaminemia (3/3 who were tested), and elevated alpha-ketoglutarate in the urine (2/4 who were tested).

This gene has been associated with relevant phenotype in OMIM (MIM #203740, last accessed 29 July 2026) and in Gene2Phenotype (with 'moderate' rating on the DD panel). This gene has also been associated with mitochondrial disease (MONDO:0044970) with 'Definitive' rating by the Mitochondrial Diseases GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009318)

Created: 29 Jul 2026, 7:31 p.m. | Last Modified: 29 Jul 2026, 7:31 p.m.

Panel Version: 10.16

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759

Publications

• 32383294
• 36520152

Green List (high evidence)

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. This gene is not associated with primary mitochondrial disease. Consensus opinion from the 3 specialist mitochondrial providers.

Created: 11 Oct 2023, 9:52 a.m. | Last Modified: 11 Oct 2023, 9:52 a.m.

Panel Version: 4.95

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

Created: 9 May 2023, 12:45 p.m. | Last Modified: 9 May 2023, 12:45 p.m.

Panel Version: 4.30

Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene. At least four variants have been reported in four unrelated cases, together with supportive functional studies (PMIDs: 32383294, 36520152).

Created: 9 May 2023, 12:43 p.m. | Last Modified: 9 May 2023, 12:43 p.m.

Panel Version: 4.29

Comment on list classification: Associated with relevant phenotype in OMIM. Limited association with OGDH-related mitochondrial disorder in Gen2Phen. PMID: 32383294 reported a single biallelic variant in two sibblings. Functional studies were performed on patient fibroblasts, which demonstrated reduced expression of OGDH and a reduced OGDH complex activity in comparison to the wild type. Drosophila models were constructed which supported the role of the OGDH variant in early developmental lethality.

Created: 9 Dec 2021, 5:59 p.m. | Last Modified: 9 Dec 2021, 5:59 p.m.

Panel Version: 2.66

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Two siblings reported with homozygous missense variant in this gene and global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Note previous report of an individual with developmental delay, hypotonia, and movement disorders and metabolic decompensation and biochemical evidence of OGDH deficiency but genetic testing not done.

Created: 4 Dec 2021, 2:53 a.m. | Last Modified: 4 Dec 2021, 2:53 a.m.

Panel Version: 2.63

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Developmental delay; ataxia; seizure; raised lactate

Publications

• 32383294

Green List (high evidence)