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  • Test code: 06221
  • 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 Pyruvate Dehydrogenase Deficiency Panel

Test description

The Invitae Pyruvate Dehydrogenase (PDH) Deficiency Panel analyzes 8 genes encoding proteins involved in the PDH complex; which converts pyruvate to acetyl-CoA. Primary clinical features of PDH deficiency include lactic acidosis, neurodevelopmental delays, structural abnormalities of the brain, and hypotonia. Symptoms usually manifest within the first few months of life and lead to premature death.

Genetic testing of these genes is useful for the diagnosis of patients whose clinical symptoms or biochemical findings indicate PDH deficiency. This test may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate risk assessment and carrier status of at-risk relatives.

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Primary panel (8 genes)

DLAT DLD LIAS MPC1 PDHA1 PDHB PDHX PDP1

  • pyruvate dehydrogenase E2 deficiency (DLAT)
  • dihydrolipoamide dehydrogenase, E3 deficiency (DLD)
  • lipoic acid synthetase deficiency (LIAS)
  • mitochondrial pyruvate carrier 1 deficiency (MPC1)
  • pyruvate dehydrogenase E1-Alpha deficiency (PDHA1)
  • pyruvate dehydrogenase E1-Beta deficiency (PDHB)
  • pyruvate dehydrogenase complex, E3 binding protein deficiency (PDHX)
  • pyruvate dehydrogenase phosphatase deficiency (PDP1)

Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme complex which catalyzes the rate-limiting step of aerobic glucose oxidation; a process crucial to energy metabolism. PDH deficiency is a disorder of energy failure with broad clinical heterogeneity. It is typically characterized by significant lactic acidosis, neurologic and neuromuscular deterioration, and early death. Affected individuals generally present within the first few months of life with a severe lactic acidosis and/or neurologic findings that may include seizures, ataxia, optic atrophy, peripheral neuropathy, choreoathetoid movements and/or Leigh disease. Conversely, much milder phenotypes manifesting subtle or subacute neurodegeneration have also been reported. Cognitive function ranges from normal to profoundly intellectually disabled. Premature death typically occurs by early childhood, although survival into adulthood has been documented.

The PDH complex is a complicated, highly regulated, multienzyme structure. Pathogenic variants in the structural or regulatory components can lead to reduced enzymatic activity and disease.

Gene Function
DLAT E2 subunit
DLD E3 subunit
LIAS Lipoic acid synthase Cofactor for E2 subunit
MPC1 Pyruvate transporter
PDHA1 E1 alpha subunit
PDHB E1 beta subunit
PDHX E3 binding protein provides structural connections to the E2 and E3 subunits
PDP1 Phosphatase catalytic subunit PDHC activation

Pathogenic mutations in genes involved in PDH catalytic activities cause PDH deficiency. These include genes (PDHA1, PDHB, DLAT, DLD) encoding the three principal components of the PDH complex E1, E2, E3, and the PDHX gene which encodes the E3 binding protein. The E3 binding protein provides structural connections to the E2 and E3 subunits. In addition, mutations in genes encoding mitochondrial pyruvate transporter, enzyme responsible for synthesis of lipoic acid, and an essential cofactor for PDH have also been associated with PDH deficiency.

Gene % Gene Attribution
DLAT 1%
DLD 5%
LIAS Unknown
MPC1 Unknown
PDHA1 76%
PDHB 2%
PDHX 6%
PDP1 Unknown

PDHA1-related PDH deficiency is inherited in an X-linked manner. The other causes of PDH deficiency are inherited in an autosomal recessive manner.

PDH deficiency is known as a very rare disorder, the prevalence in the general population is unknown.

PDH deficiency is indicated in individuals with elevated lactate concentrations in CSF and blood with a blood lactate:pyruvate ratio <=20.

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
DLAT NM_001931.4
DLD NM_000108.4
LIAS NM_006859.3
MPC1 NM_016098.3
PDHA1 NM_000284.3
PDHB NM_000925.3
PDHX NM_003477.2
PDP1 NM_018444.3