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  • Test code: 06217
  • 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 Dihydrolipoamide Dehydrogenase Deficiency Test

Test description

The Invitae Dihydrolipoamide Dehydrogenase (DLD) Deficiency Test analyzes the DLD gene that is associated with DLD deficiency. Clinical manifestations of DLD deficiency vary widely but is more commonly featured by life-threatening lactic acidosis, neurological problems, and liver diseases. Biochemical features of DLD deficiency include lactic acidosis, elevated urinary α-ketoglutarate and branched chain keto-acids, and increased plasma levels of branched chain amino acids, allo-isoleucine, and citrulline. This test is useful for the diagnosis of patients whose clinical symptoms or biochemical findings indicate DLD deficiency. Genetic testing of this gene 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.

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Primary panel (1 gene)
  • dihydrolipoamide dehydrogenase (DLD) deficiency

The DLD gene encodes the dihydrolipoamide dehydrogenase, or the E3 subunit, which is a component common to the 2-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and branched chain amino acid dehydrogeanse complexes. Pathogenic mutations in DLD disrupt the function of these three enzyme complexes and energy production. Reduced 2-KDH and PDH function lead to the accumulation of alpha-ketoglutarate and pyruvate, respectively, thereby contributing to lactic acidosis in affected individuals. BCKDH deficiency leads to the build up of branch chain amino acids and metabolites which are particularly toxic to the nervous system. Reduced energy production and accumulation of toxic metabolites in the cells lead to the development of liver diseases. Clinical manifestations of DLD deficiency vary widely but is more commonly includes life-threatening lactic acidosis, neurological problems, and liver diseases. Onset of symptoms ranges from infancy to adulthood. Individuals affected with early-onset DLD deficiency typically present severe infantile hypotonia and lactic acidosis and those who live to adulthood often manifest developmental and neurological deficits. Biochemical features of DLD deficiency include lactic acidosis, elevated urinary α-ketoglutarate and branched chain keto-acids, and increased plasma levels of branched chain amino acids, allo-isoleucine, and citrulline. These biochemical findings, however, may be absent or intermittent.

Biallelic pathogenic mutations are detected in > 95% of patients diagnosed with DLD deficiency.

Dihydrolipoamide dehydrogenase deficiency is inherited in an autosomal recessive manner.

The prevalence of dihydrolipoamide dehydrogenase deficiency in the general population is unknown and is likely very rare. In the Ashkenazi Jewish population, the disease frequency is estimated to be at least 1:35,000 to 1:48,000.

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
DLD NM_000108.4