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Leigh Syndrome Associated With Mitochondrial Complex I Deficiency via the NDUFS1 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
11511 NDUFS1 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11511NDUFS181406 81406,81479 $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. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Optic Atrophy (OA) is the most prevalent inherited optic neuropathy besides Leber’s hereditary optic neuropathy (LHON). Both share a common pathological hallmark, the preferential loss of retinal ganglion cells (RGCs) (Carelli et al. 2009; Yu-Wai-Man et al. 2010). OA is clinically characterized by bilateral reduction in visual acuity that progresses insidiously from early childhood (Yu-Wai-Man et al. 2011). Other symptoms include central or near central scotomas, tritanopia, variable degree of ptosis, central visual field defects and/or ophthalmalgia and optic nerve pallor. The most common OA is inherited in an autosomal dominant (AD) mode (DOA). Phenotype-genotype studies found that 20% of DOA patients develop a more severe phenotype called “DOA plus” (DOA+), which is characterized by extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts (Yu-Wai-Man et al. 2010; Amati-Bonneau et al. 2009). Disease prevalence is estimated at ~1/30,000 in most populations in the world, but in Denmark it can reach to 1/10,000 due to a founder effect (Kjer et al. 1996; Thiselton et al. 2001; Lenaers et al. 2012). Leigh syndrome (LS) is a neurodegenerative disease which is usually evident in the 1st year of life, but can occur later. Clinical symptoms often include motor and/or intellectual developmental delay, respiratory difficulties, nystagmus, opthalmoparesis, optic atrophy, ataxia, and dystonia. All these symptoms vary among patients. In the majority of the patients Mitochondrial complex I deficiency is the underlying cause of the disease (Loeffen et al. 2000; Dahl 1998). Mitochondrial complex I deficiency is the most frequently encountered mitochondrial disorder, and accounts for ~30% cases of respiratory-chain deficiency in childhood (Bénit et al. 2001; Pagniez-Mammeri et al. 2012; von Kleist-Retzow et al. 1998).

Genetics

Mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase) contains at least 45 structural subunits, 7 of which are encoded by mitochondrial DNA and 38 by nuclear DNA. NDUFS1, which encodes one of the largest proteins in this complex, is one of the mutational hot spot genes for isolated complex I deficiency (Pagniez-Mammeri et al. 2012). Mutations in this gene are also causative for LS associated with mitochondrial complex I deficiency. NDUFS1 mutations exhibit autosomal recessive inheritance (Martín et al. 2005). About fifteen causative mutations (missense, nonsense, small and gross deletions and small insertions) have been reported in NDUFS1 that are associated with Mitochondrial complex I deficiency (Human Gene Mutation Database). Complex I catalyzes electron transfer from NADH to ubiquinone that generates a proton gradient across the mitochondrial inner membrane to drive ATP synthesis (Mimaki et al. 2012). Although heterogeneous, the majority of suspected hereditary optic neuropathy patients (>60%) harbor pathogenic mutations within OPA1, and ~3% have OPA3 mutations (Ferre et al. 2009). Optic nerve degeneration or optic atrophy is present in many disorders where mitochondrial impairment is the underlying cause for the RGC pathophysiology (Yu-Wai-Man et al. 2011). Examples are Wolfram’s syndrome, Mohr-Tranebjaerg syndrome or other neuropathies associated with neurological diseases such as spinocerebellar ataxias, Friedreich’s syndrome, Charcot Marie-Tooth type 2 and 6, and Deafness-Dystonia-Optic Neuropathy syndromes (Lenaers et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

Predicting clinical sensitivity for the NDUFS1 gene is challenging due to genetic heterogeneity of optic atrophy. However, the majority of the reported causative mutations are detectable by this method. Gross deletions are not frequently reported in this gene (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the NDUFS1 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

Patients with symptoms suggestive of inherited optic neuropathy are candidates. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NDUFS1.

Gene

Official Gene Symbol OMIM ID
NDUFS1 157655
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Amati-Bonneau P, Milea D, Bonneau D, Chevrollier A, Ferré M, Guillet V, Gueguen N, Loiseau D, Crescenzo M-AP de, Verny C, Procaccio V, Lenaers G, et al. 2009. OPA1-associated disorders: phenotypes and pathophysiology. Int. J. Biochem. Cell Biol. 41: 1855–1865. PubMed ID: 19389487
  • Bénit P, Chretien D, Kadhom N, Lonlay-Debeney P de, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A, Rötig A. 2001. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am. J. Hum. Genet. 68: 1344–1352. PubMed ID: 11349233
  • Carelli V, Morgia C La, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. 2009. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1787: 518–528. PubMed ID: 19268652
  • Dahl HH. 1998. Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. American journal of human genetics 63: 1594. PubMed ID: 9837811
  • Ferré M, Bonneau D, Milea D, Chevrollier A, Verny C, Dollfus H, Ayuso C, Defoort S, Vignal C, Zanlonghi X, Charlin J-F, Kaplan J, et al. 2009. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Human Mutation 30: E692–E705. PubMed ID: 19319978
  • Human Gene Mutation Database (Bio-base).
  • Kjer B, Eiberg H, Kjer P, Rosenberg T. 1996. Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmol Scand 74: 3–7. PubMed ID: 8689476
  • Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D. 2012. Dominant optic atrophy. Orphanet J Rare Dis 7: 46–46. PubMed ID: 22776096
  • Loeffen J, Smeitink JAM, Trijbels JMF, Janssen AJM, Triepels RH, Sengers RCA, Heuvel LP Van den. 2000. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Human mutation 15: 123–134. PubMed ID: 10649489
  • Martín MA, Blázquez A, Gutierrez-Solana LG, Fernández-Moreira D, Briones P, Andreu AL, Garesse R, Campos Y, Arenas J. 2005. Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. Arch. Neurol. 62: 659–661. PubMed ID: 15824269
  • Mimaki M, Wang X, McKenzie M, Thorburn DR, Ryan MT. 2012. Understanding mitochondrial complex I assembly in health and disease. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1817: 851–862. PubMed ID: 21924235
  • Pagniez-Mammeri H, Loublier S, Legrand A, Bénit P, Rustin P, Slama A. 2012. Mitochondrial complex I deficiency of nuclear origin I. Structural genes. Mol. Genet. Metab. 105: 163–172. PubMed ID: 22142868
  • Thiselton DL, Alexander C, Morris A, Brooks S, Rosenberg T, Eiberg H, Kjer B, Kjer P, Bhattacharya SS, Votruba M. 2001. A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect. Human genetics 109: 498–502. PubMed ID: 11735024
  • von Kleist-Retzow J-C, Cormier-Daire V, Lonlay P de, Parfait B, Chretien D, Rustin P, Feingold J, Rötig A, Munnich A. 1998. A high rate (20%–30%) of parental consanguinity in cytochrome-oxidase deficiency. The American Journal of Human Genetics 63: 428–435. PubMed ID: 9683589
  • Yu-Wai-Man P, Griffiths PG, Burke A, Sellar PW, Clarke MP, Gnanaraj L, Ah-Kine D, Hudson G, Czermin B, Taylor RW, Horvath R, Chinnery PF. 2010. The Prevalence and Natural History of Dominant Optic Atrophy Due to OPA1 Mutations. Ophthalmology 117: 1538–1546.e1. PubMed ID: 20417570
  • Yu-Wai-Man P, Shankar SP, Biousse V, Miller NR, Bean LJH, Coffee B, Hegde M, Newman NJ. 2011. Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies. Ophthalmology 118: 558–563. PubMed ID: 21036400

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)


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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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