L-2-Hydroxyglutaric Aciduria Type I via the L2HGDH 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
8171 L2HGDH 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8171L2HGDH81479 81479 $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.

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

For Reflex to PGxome pricing click here.

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 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

L-2-Hydroxyglutaric Aciduria (L2HGA) is a rare inborn error of metabolism caused by a defect in the processing of L-2-hydroxyglutaric acid (L2HG). Affected individuals typically present before the age of 7 years with mild developmental or intellectual delays, epilepsy, and/or cerebellar ataxia (Topçu et al. 2004; Steenweg et al. 2010; Struys et al. 2016). The disease shows a slowly progressive course, with worsening cerebellar ataxia, dysarthria, mild to moderate intellectual disability, and characteristic brain abnormalities that can be differentiated from other leukodystrophies via MRI. The MRI results will typically show a pattern of signal abnormalities of the subcortical cerebral white matter, putamen, caudate nucleus, globus pallidus and dentate nucleus (Steenweg et al. 2010; Struys et al. 2016). Additional features that may be observed in these patients are seizures, variable macrocephaly, and pyramidal and extrapyramidal signs (Topçu et al. 2004). Due to the progressive nature of the disease, patients may lose skills, such as walking, over time (Steenweg et al. 2010). In addition, it has been reported that L2HGA patients have an increased tendency to develop malignant tumors of the central nervous system (Haliloglu et al. 2008; Struys et al. 2016). Biochemically, these patients are found to have elevated levels of L2HG in the urine, plasma, and cerebrospinal fluid. They may also show a decrease in N-acetylaspartate and choline and an increase in myo-inositol peaks via MR spectroscopy (Topçu et al. 2004).

Pathogenic variants in the SLC25A1 gene cause combined D-2- and L-2-hydroxyglutaric aciduria, leading to increased levels of both L2HG and D-2-hydroxyglutaric acid (D2HG) in body fluids (Struys et al. 2016). As enantiomeric separation is required to distinguish L2HG from D2HG, it is possible that initial biochemical test results may look similar for L2HGDH and SLC25A1 patients. Additional metabolic or molecular genetic investigations should be able to distinguish these disorders.

Genetics

L2HGA is an autosomal recessive disorder caused by pathogenic variants in the L2HGDH gene. Over 70 pathogenic variants have been described in this gene. Approximately half of the reported variants are missense variants and in-frame amino acid deletions. Nonsense and splice variants, small frameshift deletions, duplications and indels, and multi-exonic deletions have also been reported (Human Gene Mutation Database). There is no apparent genotype-phenotype correlation (Steenweg et al. 2010). The only two variants commonly reported in different populations are c.905C>T (p.Pro302Leu) and the frameshift variant c.530_533delinsATT (p.Pro177Hisfs*6). In addition, the variant c.241A>G (p.Lys81Glu) has been reported to be a founder mutation in the Tunisian population (Jellouli et al. 2014).

The L2HGDH gene encodes the L-2-hydroxyglutarate dehydrogenase enzyme, which converts the metabolite L-2-hydroxyglutaric acid to 2-ketoglutarate, an intermediate in the citric acid cycle (Struys et al. 2016).

Clinical Sensitivity - Sequencing with CNV PGxome

Based on a collective total of patients with elevated L2HG levels reported in several studies, the clinical sensitivity of this test is expected to range from approximately 83% to nearly 100% (Topçu et al. 2004; Vilarinho et al. 2005; Sass et al. 2008; Vilarinho et al. 2010). Several patients were reported to carry large deletions, which would not be detectable via sequencing (Steenweg et al. 2010).

Testing Strategy

This test provides full coverage of all coding exons of the L2HGDH 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.

This test also includes coverage for the c.906+354G>A intronic variant, as well as ~10 bp of adjacent sequence.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with clinical and biochemical features consistent with L2HGA are good candidates for this test. Family members of patients who have known L2HGDH pathogenic variants are also good candidates. We will also sequence the L2HGDH gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
L2HGDH 609584
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
L-2-Hydroxyglutaric Aciduria AR 236792

Citations

  • Haliloglu G. et al. 2008. Neuropediatrics. 39: 119-22. PubMed ID: 18671189
  • Human Gene Mutation Database (Bio-base).
  • Jellouli N.K. et al. 2014. Journal of Human Genetics. 59: 216-22. PubMed ID: 24573090
  • Sass J.O. et al. 2008. Journal of Inherited Metabolic Disease. 31 Suppl 2: S275-9. PubMed ID: 18415700
  • Steenweg M.E. et al. 2010. Human Mutation. 31: 380-90. PubMed ID: 20052767
  • 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.
  • Top├žu M. et al. 2004. Human Molecular Genetics. 13: 2803-11. PubMed ID: 15385440
  • Vilarinho L. et al. 2005. Human Mutation. 26: 395-6. PubMed ID: 16134148
  • Vilarinho L. et al. 2010. Journal of Human Genetics. 55: 55-8. PubMed ID: 19911013

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.

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

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ORDER OPTIONS

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