The relationship between D2HGDH and D2HGDH-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 2, 2023. The D2HGDH gene encodes D-2-hydroxyglutarate dehydrogenase, which is a mitochondrial enzyme that converts D-2-hydroxyglutarate into 2-ketoglutarate.
The D2HGDH gene was first reported in relation to D2HGDH-related primary mitochondrial disease in 2005 (PMID: 15609246). D2HGDH has been associated with a single disease entity to date, autosomal recessive D-2-hydroxyglutaric aciduria [OMIM#600721]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as D2HGDH-related primary mitochondrial disease.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants (four missense, three splice, two frameshift, and one multi-exon deletion) identified in seven unrelated cases from five publications (PMIDs: 15609246, 16081310, 19169842, 20020533, 31431883). Clinical features in affected individuals are variable and range from early infantile-onset epileptic encephalopathy with hypotonia, delayed cerebral visual development, cardiomyopathy, dysmorphic facial features, and abnormalities on brain imaging to variable developmental delay and hypotonia. Biochemical lab abnormalities include elevated D-2-hydroxyglutaric acid (D-2-HG) in urine, plasma, and/or cerebrospinal fluid (CSF).
The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in non-patient cells showing impaired D‐2‐HGDH enzyme activity, and a C. elegans model of D2HGDH deficiency that showed elevated 2-HG levels and mitochondrial defects compared to wild-type animals (PMIDs: 33340416, 30908763, 37043428).
In summary, there is definitive evidence to support the relationship between D2HGDH and D2HGDH-related 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 October 2, 2023 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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