Submission Details

The relationship between IDH2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 30, 2023. The IDH2 gene encodes mitochondrial NADP(+)-specific isocitrate dehydrogenase, which is a mitochondrial NADP-dependent isocitrate dehydrogenase that catalyzes oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the Krebs tricarboxylic acid cycle, producing NADPH.

The IDH2 gene was first reported in relation to autosomal dominant primary mitochondrial disease in 2010 (PMID: 20847235). While various names have been given to the constellation of features seen in those with IDH2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the IDH2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique missense variants affecting the same amino acid, identified in sixteen individuals from three publications (PMIDs: 20847235, 24049096, 35359529). The recurrent p.Arg140Gln variant was reported in 15 individuals, including in a de novo state in at least seven and a mosaic state in two. The p.Arg140Gly variant was reported in one individual. To our knowledge, variants affecting other residues have not been reported in association with primary mitochondrial disease. Defects of this protein have been associated with a neurometabolic disorder characterized by elevated D-2-hydroxyglutarate (D-2-HG). Additional features can include developmental delay, epilepsy, hypotonia, cardiomyopathy, and dysmorphic features. Somatic variants affecting Arg140 and Arg172 are found in acute myeloid leukemias, myelodysplastic syndromes, angioimmunoblastic T-cell lymphomas, brain tumors, and other cancers and result in elevated D-2HG, but cancer is not usually a feature of this condition. The mechanism of disease involves loss of the protein’s normal function to convert isocitrate to α-ketoglutarate and acquisition of a gain of function to convert α-ketoglutarate to D-2-HG. This gene-disease relationship is also supported by a biochemical function in the Krebs cycle shared with other genes associated with primary mitochondrial disease and recapitulation of elevated levels of D-2-HG and clinical features of the disorder in two knock-in mouse models with the p.Arg140Gln variant (PMIDs: 33340416, 24589777, 27469509). Turning off expression of the mutant protein and treatment with a small molecule inhibitor of IDH2 p.Arg149Gln also led to rescue of the phenotype in these models.

In summary, there is definitive evidence to support the relationship between IDH2 and autosomal dominant primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 30, 2023 (SOP Version 9).