DNA icon

Mitochondrial Complex I Deficiency via the NDUFS4 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
8675 NDUFS4 81404 81404,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8675NDUFS481404 81404,81479 $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 deficiency of the first and largest of the oxidative phosphorylation complexes (Fassone and Rahman 2012). Isolated mitochondrial CI deficiency is the most frequently reported childhood-onset mitochondrial disease, which may account for roughly one-third of all oxidative phosphorylation (OXPHOS) disorders (Skladal et al. 2003; Scaglia et al. 2004).

Significant clinical and genetic heterogeneity is observed among patients with inherited CI deficiency. The majority of patients present with a severe, rapidly progressive disease course within the first year of life. Organs with high energy requirements (such as the brain, heart, skeletal muscles, and/or eyes) are often the primary affected targets, and the most common clinical presentations include Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, hypertrophic cardiomyopathy, and exercise intolerance (Fassone and Rahman 2012). Similar to other OXPHOS disorders, overproduction of lactic acid is a prevalent finding in patients with CI deficiency.

NDUFS4-associated mitochondrial CI deficiency has been reported in approximately thirty patients to date. The majority of patients presented during the neonatal or infantile stages with Leigh syndrome (LS), a severe, progressive encephalopathy characterized by a distinct set of diagnostic criteria (Rahman and Thorburn 2015). LS symptoms include 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 (Lake et al. 2015; Anderson et al. 2008). Leigh-like syndrome, which describes a similar clinical presentation in which one or more of these diagnostic characteristics is atypical, has also been reported in patients with pathogenic variants in NDUFS4 (Petruzzella et al. 2001; Scacco et al. 2003).

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 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; Sazanov 2015). 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, and at least 33 genes have been linked to this disease to date (Fassone and Rahman 2012).

NDUFS4-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. The NDUFS4 gene encodes a subunit of the mitochondrial complex I that must be phosphorylated by cAMP-dependent protein kinase for activation of the complex (Papa et al. 2002). At least 15 causative variants have been reported in this gene, including missense, nonsense, and splicing variants; small deletions and duplications; one indel; and two gross deletions (Human Gene Mutation Database).

At least two NDUFS4 founder pathogenic variants have been described. One single nucleotide deletion (c.462delA) has a carrier frequency of 1 in 1,000 in the Ashkenazi Jewish population (Anderson et al. 2008). An aberrant splicing variant, c.99-1G>A, has been reported in multiple families of Moroccan ancestry (Assouline et al. 2012; Bénit et al. 2003). Other variants, such as c.291delG (p.Trp97*), have been identified in multiple affected individuals from unrelated families, possibly indicating the presence of additional founder pathogenic variants in this gene (Budde et al. 2000; Assouline et al. 2012; Scacco et al. 2003).

Clinical Sensitivity - Sequencing with CNV PGxome

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFS4-related mitochondrial complex I deficiency is difficult to estimate.

Testing Strategy

This test provides full coverage of all coding exons of the NDUFS4 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

NDUFS4 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. Additionally, NDUFS4 sequencing could be considered for patients of Moroccan or Ashkenazi Jewish ancestry who present with Leigh or Leigh-like syndrome. We will also sequence the NDUFS4 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
NDUFS4 602694
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Leigh Syndrome AR 256000
Mitochondrial Complex I Deficiency AR 252010

Related Tests

Name
NDUFA2-Related Leigh Syndrome (LS) via the NDUFA2 Gene
SURF1-Related Leigh Syndrome (LS) via the SURF1 Gene
Comprehensive Cardiology Panel
Leigh Syndrome Associated with Isolated Complex I Deficiency via the NDUFA12 Gene
Leigh Syndrome Associated with Mitochondrial Complex I Deficiency via the NDUFA9 Gene
Leigh Syndrome Associated With Mitochondrial Complex I Deficiency via the NDUFAF2 Gene
Leigh Syndrome Associated with Mitochondrial Complex I Deficiency via the NDUFS7 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 NDUFS6 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
Mitochondrial Complex III Deficiency Panel (Nuclear Genes)
Mitochondrial Complex IV Deficiency via the COX15 Gene
Optic Atrophy Panel

Citations

  • Anderson S.L. et al. 2008. Journal of Inherited Metabolic Diseases. 31 (Suppl 2): S461-7. PubMed ID: 19107570
  • Assouline Z. et al. 2012. Biochimica et Biophysica Acta. 1822:1062-9. PubMed ID: 22326555
  • Bénit P. et al. 2003. Human Genetics. 112:563-6. PubMed ID: 12616398
  • Budde S.M. et al. 2000. Biochemical and Biophysical Research Communications. 275:63-8. PubMed ID: 10944442
  • Fassone and Rahman. 2012. PubMed ID: 22972949
  • Human Gene Mutation Database (Bio-base).
  • Lake et al. 2015. PubMed ID: 25978847
  • Papa S. et al. 2002. Bioscience Reports. 22:3-16. PubMed ID: 12418547
  • Petruzzella V. et al. 2001. Human Molecular Genetics. 10:529-35. PubMed ID: 11181577
  • Rahman S. and Thorburn D. 2015. Nuclear Gene-Encoded Leigh Syndrome Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 26425749
  • Sazanov L.A. et al. 2015. Nature Reviews Molecular Cellular Biology. 16:375-88. PubMed ID: 25991374
  • Scacco S. et al. 2003. Journal of Biological Chemistry. 278:44161-7. PubMed ID: 12944388
  • Scaglia et al. 2004. PubMed ID: 15466086
  • Skladal et al. 2003. PubMed ID: 12805096

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

loading Loading... ×

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.
Total Price: $
×
Copy Text to Clipboard
×