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Mitochondrial Complex I Deficiency via the NDUFS6 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8899 NDUFS6 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8899NDUFS681479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Kym Bliven, PhD

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).

In the majority of reported patients with NDUFS6-associated mitochondrial CI deficiency, affected individuals were diagnosed with severe neonatal or infantile-onset lactic acidosis (Kirby et al. 2004; Haack et al. 2012; Spiegel et al. 2009; Pronicka et al. 2016). Additional symptoms included hypotonia, nystagmus, and/or seizures.

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.

NDUFS6-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. The NDUFS6 gene encodes for a zinc-binding subunit of the mitochondrial CI (Kmita et al. 2015). Six pathogenic variants have been reported in this gene to date: one missense variant, one nonsense variant, one splicing variant, one small deletion, one small indel, and one large deletion (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFS6-related mitochondrial complex I deficiency is difficult to estimate.

Testing Strategy

This test provides full coverage of all coding exons of the NDUFS6 gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

NDUFS6 sequencing should be considered for patients who present with symptoms consistent with mitochondrial complex I (CI) deficiency or for individuals with a family history of mitochondrial CI deficiency. We will also sequence the NDUFS6 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
NDUFS6 603848
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mitochondrial Complex I Deficiency AR 252010

Related Tests

Name
Leigh Syndrome Associated With Mitochondrial Complex I Deficiency via the NDUFAF2 Gene
Mitochondrial Complex I Deficiency Panel (Nuclear Genes)
Mitochondrial Complex I Deficiency via the NDUFA11 Gene
Mitochondrial Complex I Deficiency via the NDUFA1 Gene
Mitochondrial Complex I Deficiency via the NDUFAF1 Gene
Mitochondrial Complex I Deficiency via the NDUFAF4 Gene
Mitochondrial Complex I Deficiency via the NDUFB3 Gene
Mitochondrial Complex I Deficiency via the NDUFB9 Gene
Mitochondrial Complex I Deficiency via the NDUFS4 Gene
Mitochondrial Complex I Deficiency via the NDUFV1 Gene
Mitochondrial Complex I Deficiency via the NDUFV2 Gene
Mitochondrial Complex I Deficiency via the NUBPL Gene

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. 49:83-9. PubMed ID: 22200994
  • Human Gene Mutation Database (Bio-base).
  • Kirby D.M. et al. 2004. Journal of Clinical Investigation. 114:837-45. PubMed ID: 15372108
  • Kmita K. et al. 2015. Proceedings of the National Academy of Sciences U S A. 112:5685-90. PubMed ID: 25902503
  • Lake et al. 2015. PubMed ID: 25978847
  • Pronicka E. et al. 2016. Journal of Translational Medicine. 14:174. PubMed ID: 27290639
  • Rahman and Thorburn. 2015. PubMed ID: 26425749
  • Scaglia et al. 2004. PubMed ID: 15466086
  • Skladal et al. 2003. PubMed ID: 12805096
  • Spiegel R. et al. 2009. European Journal of Human Genetics. 17:1200-3. PubMed ID: 19259137

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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