The Invitae 2-Hydroxyglutaric Aciduria Panel analyzes 4 genes that are associated with elevations of the D-form, L-form, or both forms of 2-hydroxyglutaric acid in urine. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives.
D2HGDH IDH2 L2HGDH SLC25A1
D2HGDH IDH2 L2HGDH SLC25A1
For a broader analysis of the genetics of organic acidemias:
|D2HGDH||D-2-hydroxyglutaric aciduria type I|
|IDH2||D-2-hydroxyglutaric aciduria type II|
2-hydroxyglutaric aciduria is a cerebral organic acidemia that is characterized by the elevation of 2-hydroxyglutaric acid in the urine. Depending on the underlying genetic cause, the D-form, L-form, or both forms of 2-hydroxyglutaric acid may be elevated. Routine urine organic acid analysis cannot distinguish between the different forms of the disorder.
Patients with L-2-hydroxyglutaric aciduria may have slight intellectual disability and psychomotor delay in infancy or early childhood. As the disease progresses, patient typically have seizures, progressive ataxia, pyramidal and extrapyramidal signs, and progressive intellectual disability. Roughly half of patients have progressive macrocephaly. Patients will also have characteristic findings on neuroimaging such as swelling of the subcortical white matter, severe cerebellar atrophy with loss of arcuate fibers. On T2-weighted images, the dentate nuclei and globi pallidi will show increased signal intensity. Various types of malignant brain tumors have also been reported in patients. Riboflavin may help reduce neurological symptoms and seizures are generally well controlled.
Patients with D-2-hydroxyglutaric aciduria show a broad spectrum in severity from severe neonatal onset disease to asymptomatic. Most patients present with the severe form of the disorder which includes early onset epileptic encephalopathy, lack of psychomotor development, severe hypotonia, cortical blindness, and early death. Some patients may also have cardiomyopathy. Neuroradiological findings include ventriculomegaly, delayed gyration, delayed myelination, and cysts in the caudate nucleus. The epilepsy is usually intractable. Milder patients may have mild developmental delay, speech delay, and febrile convulsions.
Patients with D,L-2-hydroxyglutaric aciduria have developmental delay, hypotonia, seizures and early death. Some patients have been reported with dysmorphic features, fatigable weakness, jerking movements, central apnea and respiratory failure, lactic acidosis, congenital heart defects, and optic nerve hypoplasia. Abnormal findings on brain imaging studies have been reported such as ventriculomegaly, cerebral volume loss, hypoplasia of the corpus callosum, and periventricular frontal lobe cysts.
For patients with a biochemical diagnosis of D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, or D,L-2-hydroxyglutaric aciduria, we estimate that greater than 95% of patients will have pathogenic findings in one of the genes tested.
Most forms of 2-hydroxyglutaric aciduria are inherited in an autosomal recessive manner. However, D,2-hydroxyglutaric aciduria due to pathogenic variants in IDH2 is inherited in an autosomal dominant manner.
All forms of 2-hydroxyglutaric aciduria are rare and the exact prevalence is unknown.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|