Mitochondrial Complex I Deficiency Panel (Nuclear Genes)

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3455 ACAD9 81479,81479 Order Options and Pricing
FOXRED1 81479,81479
MTFMT 81479,81479
NDUFA1 81404,81479
NDUFA10 81479,81479
NDUFA11 81479,81479
NDUFA12 81479,81479
NDUFA13 81479,81479
NDUFA2 81479,81479
NDUFA9 81479,81479
NDUFAF1 81479,81479
NDUFAF2 81404,81479
NDUFAF3 81479,81479
NDUFAF4 81479,81479
NDUFAF5 81479,81479
NDUFAF6 81479,81479
NDUFB3 81479,81479
NDUFB9 81479,81479
NDUFS1 81406,81479
NDUFS2 81479,81479
NDUFS3 81479,81479
NDUFS4 81404,81479
NDUFS6 81479,81479
NDUFS7 81405,81479
NDUFS8 81405,81479
NDUFV1 81405,81479
NDUFV2 81479,81479
NUBPL 81479,81479
POLG 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3455Genes x (29)81479 81404, 81405, 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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.

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

Mitochondrial complex I (CI) deficiency is characterized by a primary deficiency of the first and largest oxidative phosphorylation complex (Fassone and Rahman 2012). Primary mitochondrial CI deficiency accounts for roughly one-third of all oxidative phosphorylation disorders and is the most frequently reported childhood-onset mitochondrial disease (Skladal et al. 2003; Scaglia et al. 2004).

The majority of CI-deficient patients present within the first year of life (Distelmaier et al. 2009). Respiratory infections, gastrointestinal disease, or long periods of fasting may trigger the initial symptoms of this disorder and stimulate additional episodes, leading to rapid deterioration of the patient’s condition. Similar to other OXPHOS disorders, recurrent lactic acidosis is a prevalent finding in patients with CI deficiency. Additional clinical symptoms, which can involve single or multiple organ systems, may be highly heterogeneous. The most common clinical presentations in patients with nuclear-encoded CI deficiency include Leigh/Leigh-like syndrome (LS/LLS), leukoencephalopathy with macrocephaly, fatal infantile lactic acidosis, hypertrophic cardiomyopathy, and hepatopathy with renal tubulopathy (Fassone and Rahman 2012; Distelmaier et al. 2009). LS is a severe, progressive encephalopathy characterized by psychomotor delay or regression, isolated or combined mitochondrial complex deficiencies, elevated levels of lactate in the blood and/or cerebral spinal fluid, bilateral symmetrical lesions in the brainstem and basal ganglia, and neurologic manifestations such as hypotonia or ataxia (Rahman and Thorburn 2015; Lake et al. 2015).

At the present time, although over 30 genes have been linked to CI deficiency to date (see ‘Genetics,’ below), clear genotype-phenotype correlations are lacking.

Genetics

The mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase) is composed of at least 45 structural subunits (Fassone and Rahman 2012). 38 of these subunits are encoded by nuclear DNA, and 7 (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6) are encoded by mitochondrial DNA. The resulting holoenzyme complex plays a critical role in redox-driven proton translocation, which ultimately results in synthesis of adenosine triphosphate (ATP). Due to the many structural and accessory subunits required to support the assembly and function of complex I, mitochondrial CI deficiency is a genetically heterogeneous disorder. At least 33 genes have been linked to this disease to date. Causative variants in the nuclear genes are predominantly inherited in an autosomal recessive manner with the exception of NDUFA1, which has an X-linked recessive mode of inheritance. In contrast, causative variants in mitochondrial-encoded genes are inherited in a maternal manner.

This NextGen Panel covers 29 nuclear genes (ACAD9, FOXRED1, MTFMT, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFA2, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NUBPL, and POLG) that have been associated with primary mitochondrial complex I deficiency. This panel does not cover the mitochondrial-encoded genes known to be associated with this disorder (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6).

NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFA2, NDUFA9, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, and NDUFV2 encode for subunits of CI, while NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, ACAD9, and FOXRED1 encode assembly factors of the complex (Fassone and Rahman 2012). The NUBPL gene encodes for an additional assembly protein that plays a role in CI incorporation of the eight iron-sulfur clusters necessary for electron transfer activity.

Although pathogenic variants in POLG or MTFMT more commonly result in a combined oxidative phosphorylation deficiency, several patients with defects in these genes presented with a primary CI defect (Swalwell et al. 2011; Haack et al. 2012). Therefore, POLG and MTFMT have also been included in this panel. POLG encodes for the catalytic subunit of DNA polymerase gamma, while MTFMT encodes for the mitochondrial methionyl-tRNA formyltransferase.

See individual gene test descriptions for information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

Approximately 25% of CI-deficient cases have defects in nuclear-encoded genes, while another ~25% carry a pathogenic variant in a mitochondrial-encoded gene (Fassone and Rahman 2012). In patients with a molecular diagnosis, ~60% have defects in genes that encode core subunits of CI, while the remaining ~40% have defects in genes that encode accessory subunits.

Causative variants in many of the genes in this NextGen Panel have only been documented in one or two families to date, making clinical sensitivity difficult to estimate. No large cohort studies have been reported. In a small cohort of ten unrelated individuals with complex I deficiency, exome sequencing revealed probable causative variants in NDUFS3, ACAD9, NDUFS8, NDUFB3, or MTFMT in seven of the ten patients (70%; Haack et al. 2012).

Large deletions/duplications have been reported in NDUFAF2, NDUFS1, NDUFS4, NDUFS6, NUBPL, and POLG (Human Gene Mutation Database). Although we cannot estimate precisely clinical sensitivity at this time, large deletions and duplications in these genes appear to be a rare cause of CI deficiency.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Two intronic variants are also covered in this test: c.17-1167C>G in the NDUFS7 gene and c.815-27T>C in the NUBPL gene (Lebon et al. 2007; Tucker et al. 2012).

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

Candidates for this test include patients with a primary deficiency of mitochondrial complex I, or those who present with symptoms consistent with primary complex I deficiency.

Related Test

Name
PGxome®

Citations

  • Distelmaier F. et al. 2009. Brain. 132:833-42. PubMed ID: 19336460
  • Fassone and Rahman. 2012. PubMed ID: 22972949
  • Haack T.B. et al. 2012. Journal of Medical Genetics. 49:277-83. PubMed ID: 22499348
  • Human Gene Mutation Database (Bio-base).
  • Lake et al. 2015. PubMed ID: 25978847
  • Lebon S. et al. 2007. Molecular Genetics and Metabolism. 92:104-8. PubMed ID: 17604671
  • Rahman and Thorburn. 2015. PubMed ID: 26425749
  • Scaglia et al. 2004. PubMed ID: 15466086
  • Skladal et al. 2003. PubMed ID: 12805096
  • Swalwell H. et al. 2011. European Journal of Human Genetics. 19:769-75. PubMed ID: 21364701
  • Tucker E.J. et al. 2012. Human Mutation. 33:411-8. PubMed ID: 22072591

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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STAT and Prenatal Test Options are not available with Patient Plus.

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