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  • Test code: 06215
  • 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 2-Ketoglutarate Dehydrogenase Deficiency Panel

Test description

The Invitae 2-Ketoglutarate Dehydrogenase Deficiency Panel analyzes up to 4 genes that are associated with 2-ketoglutarate dehydrogenase (2-KDH) deficiency. This test is useful for the diagnosis of patients whose clinical symptoms or biochemical findings indicate 2-KDH deficiency. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives.

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Primary panel (3 genes)
Add-on Alpha-ketoadipic Acid Dehydrogenase Deficiency Gene (1 gene)

The DHTKD1 gene encodes the alpha-ketoadipic acid dehydrogenase (KAADH), a protein homolog of the alpha-ketoglutarate dehydrogenase, defining the KAADH complex as an alpha-ketoacid dehydrogenase complex . The KAADH complex functions in the catabolic pathway of lysine, hydroxylysine, and tryptophan. Defects in this protein have been suggested to lead to an increase excretion of alpha-ketoadipic acid and alpha-aminoadipic acid.

2-KDH deficiency and KAADH deficiency share overlapping general features including metabolic acidosis, hypotonia, and seizures. This gene can be added at no additional charge.

DHTKD1

  • alpha-ketoglutarate dehydrogenase, E1 deficiency (OGDH)
  • dihydrolipoamide dehydrogenase, E3 deficiency (DLD)
  • mitochondrial thiamine pyrophosphate carrier deficiency (SLC25A19)

2-KDH deficiency is a group of autosomal recessive inherited metabolic disorders that are caused by a deficiency in one of three enzymes involved in the metabolism of 2-ketoglutarate. The 2-KDH complex is analogous to the pyruvate dehydrogenase (PDH) complex. Similar to PDH complex deficiency, symptoms of 2-KDH deficiency manifest in the neonatal period and early childhood, primarily include developmental delay, hypotonia, ataxia, opisthotonos and less frequently, seizures and extrapyramidal dysfunction.

OGDH deficiency
The OGDH gene encodes the alpha-ketoglutarate dehydrogenase, also known as the E1 subunit. Deficiency of alpha-ketoglutarate dehydrogenase is characterized by toxic accumulation of lactic acid which leads to neurological problems including hypotonia, metabolic acidosis, and hyperlactatemia.

DLD deficiency
The DLD gene encodes the dihydrolipoamide dehydrogenase, or the E3 subunit, which is a component common to the 2-KDH, pyruvate dehydrogenase, and branched chain keto acid dehydrogenase complexes. Clinical manifestation of DLD deficiency vary widely but is more commonly featured by life-threatening lactic acidosis, neurological problems, and liver diseases. Pathogenic mutations in DLD disrupt the function of these three enzyme complexes and energy production. Reduced 2-KDH and PDH function also 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.

SLC25A19 deficiency
Pathogenic mutations in SLC25A19 causes Amish lethal microcephaly which is characterized by tenfold elevation of urinary 2-ketoglutarate level. In addition to severe microcephaly, these patients often survive to only a few months of age.

DLD, OGDH, and SLC25A19 are the only genes known to be associated with 2-KDH. However, due to the rarity of this condition, the percent of 2-KDH attributed to pathogenic variants in these genes is currently unknown.

2-KDH deficiency is inherited in an autosomal recessive manner.

Alpha-ketoglutarate dehydrogenase deficiency is a rare disorder with an unknown prevalence in the general population. In the Ashkenazi Jewish population, the prevalence of DLD deficiency is estimated to be at least 1:35,000 to 1:48,000. In the Old-Order Amish population, Amish lethal microcephaly may be as high as 1 in 500 births.

This test may be appropriate for patients with:

  • elevations of 2-ketoglutarate on urine organic acids with or without increased urinary levels of TCA intermediates
  • elevated blood lactate levels but CSF lactate/pyruvate ratios may be elevated or normal
  • hypotonia, developmental delay, ataxia, opisthotonos and less commonly seizures

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
DHTKD1 NM_018706.6
DLD NM_000108.4
OGDH NM_002541.3
SLC25A19 NM_021734.4