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D-2-Hydroxyglutaric Aciduria Type I via the D2HGDH Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8333 D2HGDH 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8333D2HGDH81479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

D-2-Hydroxlglutaric Aciduria Type I (D2HGA-I) is a rare inborn error of metabolism caused by a defect in the processing of D-2-hydroxyglutaric acid (D2HG). Affected individuals have ranged from severely affected to asymptomatic. The patients with severe D2HGA-I have presented in infancy or early childhood, usually by 6 years of age, with early infantile-onset epileptic encephalopathy with hypotonia, cerebral visual failure or delayed cerebral visual development, developmental delay, episodic vomiting, stridor, apnea and facial dysmorphism. Disturbed cerebral maturation, white abnormalities and subependymal cysts are often observed on magnetic resonance images (MRIs). Spondyloenchondrodysplasia has also been reported. Symptoms are generally slowly progressive, but non-fatal in most patients (Misra et al. 2005; Struys et al. 2005a; Haliloglu et al. 2009; Struys et al. 2016). More mildly affected patients have also been reported. These patients typically have a more variable clinical presentation which may also include macrocephaly and peripheral neuropathy. In addition, they tend to have less consistent MRI findings (Struys et al. 2005a; Haliloglu et al. 2009). Some asymptomatic individuals have been identified via family screening (Misra et al. 2005). Biochemically, all D2HGA-I patients are found to have increased levels of D2HG in body fluids (urine, plasma and cerebral spinal fluid), and decreased activity of the D-2-hydroxyglutarate dehydrogenase enzyme (Struys et al. 2005a; Kranendijk et al. 2010; Struys et al. 2016).

Pathogenic variants in other genes may also lead to increased levels of D2HG in body fluids. These genes include IDH1, IDH2, SLC25A1, and possibly ALDH5A1 and ETFA, ETFB and ETFDH (Struys et al. 2006; Struys et al. 2016). Additional metabolic investigations may be able to distinguish the various causes of elevated D2HG levels.

Genetics

D2HGA-I is an autosomal recessive disorder caused by pathogenic variants in the D2HGDH gene. Over 30 pathogenic variants have been described in this gene. Approximately two-thirds of the reported variants are missense variants, though splice variants, small frameshift deletions and duplications, and multi-exonic deletions have also been reported (Human Gene Mutation Database). There is no apparent genotype-phenotype correlation, and thus far there are no commonly reported pathogenic variants (Kranendijk et al. 2010).

The D2HGDH gene encodes the D-2-hydroxyglutarate dehydrogenase enzyme, which converts the metabolite D-2-hydroxyglutaric acid to 2-ketoglutarate, an intermediate in the citric acid cycle (Struys et al. 2005b; Struys et al. 2016).

Clinical Sensitivity - Sequencing with CNV PGxome

In the largest cohort published of patients with elevated D2HG levels, 24 out of 50 patients were found to be homozygous or compound heterozygous for presumed pathogenic D2HGDH sequence variants. Two of these patients were found to harbor multi-exon deletions. Therefore, 46 D2HGDH alleles detectable by sequencing were identified out of a total of 100 alleles, for a sensitivity of ~46%. Enzyme activity was only studied in 25 of these patients, and D2HGDH activity was only found to be decreased in 7 of the 25. However, all 7 of these patients were found to harbor two D2HGDH sequence variants, suggesting a clinical sensitivity closer to 100% in patients with a confirmed enzyme defect (Kranendijk et al. 2010). In another study, two unrelated patients with elevated D2HG in body fluids and a confirmed enzymatic defect were found to carry presumed pathogenic D2HGDH variants on both alleles (Struys et al. 2005b).

Testing Strategy

This test provides full coverage of all coding exons of the D2HGDH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

This testing also includes coverage for the intronic splice variant c.293-23A>G.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Patients with clinical and biochemical features consistent with D2HGA-I are good candidates for this test, particularly if they have been shown to have reduced D2HGDH enzyme activity. Family members of patients who have known D2HGDH pathogenic variants are also good candidates. We will also sequence the D2HGDH gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
D2HGDH 609186
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
D-2-Alpha Hydroxyglutaric Aciduria AR 600721

Citations

  • Haliloglu G. et al. 2009. Journal of Inherited Metabolic Disease. 32 Suppl 1: S21-5. PubMed ID: 19169842
  • Human Gene Mutation Database (Bio-base).
  • Kranendijk M. et al. 2010. Human Mutation. 31: 279-83. PubMed ID: 20020533
  • Misra V.K. et al. 2005. Molecular Genetics and Metabolism. 86: 200-5. PubMed ID: 16081310
  • Struys E.A. et al. 2005a. Annals of Neurology. 58: 626-30. PubMed ID: PubMed ID: 16037974
  • Struys E.A. et al. 2005b. American Journal of Human Genetics. 76: 358-60. PubMed ID: 15609246
  • Struys E.A. et al. 2006. Molecular Genetics and Metabolism. 88: 53-7. PubMed ID: 16442322
  • Struys E.A., van der Knapp M.S., Salomons G.S. 2016. 2-Hydroxyglutaric Acidurias. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 145-147.

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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