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  • Test code: 06168
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Ketogenesis Disorders Panel

Test description

The Invitae Ketogenesis Disorders Panel analyzes two genes associated with ketone body synthesis. This test may be appropriate for anyone in whom a ketogenesis defect is suspected based on clinical symptoms, such as recurrent, unexplained episodes of hypoglycemia, laboratory findings or a combination of both.

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Primary panel (2 genes)

Alternative tests to consider

For a broader analysis of the genetics of fatty acid defects or organic acidemias:

  • HMG-CoA lyase deficiency
  • HMG-CoA synthase deficiency

Ketones are an alternative fuel source used by many tissues during times of glucose scarcity. They are a product of fat metabolism as they are derived from acetyl-CoA generated during fatty acid oxidation. Ketogenesis occurs in a four step pathway with HMG-CoA synthase catalyzing the second step, and HMG-CoA lyase catalyzing the third step (additionally, HMG-CoA lyase is also involved in the final step of leucine catabolism). Ketones are then released by the liver for consumption by other tissues, especially the brain.

Clinical symptoms of ketogenesis defects typically include vomiting, hypoketotic hypoglycemia, metabolic acidosis, liver dysfunction, coma and even death, if untreated. Most affected individuals present prior to one year of age with a hypoglycemic crisis, and up to one third may become symptomatic in the neonatal period. Later presentations, including adulthood, have also been reported. Long term consequences such as cognitive deficits and seizures can occur, and cardiomyopathy has also been reported. These consequences are secondary to hypoglycemia and metabolic acidosis. Recurrent episodes of decompensation can occur and are often precipitated by a period that combines fasting with physiologic stress, such as illness. These periods increase the metabolic rate and are often accompanied by a diminished appetite so the body turns to fats and ketones for energy. The long-term prognosis for ketogenesis defects is generally good once a diagnosis is obtained and interventions such as dietary modifications, avoidance of fasting and illness protocols are implemented.

HMG-CoA lyase deficiency and HMG-CoA synthase deficiency are inherited in an autosomal recessive manner.

Both HMG-CoA synthase and HMG-CoA lyase are rare metabolic defects, but are likely underdiagnosed.

HMG-CoA lyase is more commonly observed Saudi Arabia due to the pathogenic founder variant c.122 G>A (p.Arg41Gln). Additionally, there is a founder variant on the Iberian peninsula c.109G>T (p.Glu37*).

This test may be appropriate for:

  • patients who present with lethargy and hypoketotic hypoglycemia, especially during infancy
  • infants with an elevated C5-OH acylcarntine on newborn screening

Assay and technical information

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
HMGCL NM_000191.2
HMGCS2 NM_005518.3