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Leber Hereditary Optic Neuropathy (LHON) - Targeted Testing for 3 Common Pathogenic Variants

Summary and Pricing

Test Method

Sanger Sequencing- LHON Targeted Mitochondrial Variants
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
15667 MT-ND1 81479 Order Options and Pricing
MT-ND4 81401
MT-ND6 81401
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
15667Genes x (3)81479 81401(x2), 81479(x1) $580 Order Options and Pricing

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

Turnaround Time

12 days on average for standard orders or 8 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

Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that results from respiratory chain dysfunction in the retinal ganglion cells, ultimately leading to progressive bilateral loss of vision (Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353; Moster et al. 2016. PubMed ID: 27459664). Vision loss may be sequential; patients may initially be affected in only one eye, but the second may develop vision loss within ~8 weeks (Riordan-Eva et al. 1995. PubMed ID: 7735876). Onset may occur at any age, but for males often peaks in the second or third decade of life (Riordan-Eva et al. 1995. PubMed ID: 7735876; Lopez Sanchez et al. 2021. PubMed ID: 34670133).

The prevalence of LHON with a molecularly-confirmed diagnosis due to one of the three most common pathogenic variants has been estimated to be ~1:45,000 in European populations (Mascialino et al. 2012. PubMed ID: 21928272). LHON variants may display significant incomplete penetrance, but the exact percentage may vary from family to family and also over generational time, possibly due to other contributing genetic or environmental factors (Lopez Sanchez et al. 2021. PubMed ID: 34670133; Kirkman et al. 2009. PubMed ID: 19525327). A gender bias has been reported, with males affected more often than females, although the cause of this is not yet understood (Lopez Sanchez et al. 2021. PubMed ID: 34670133; Puomila et al. 2007. PubMed ID: 17406640; Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353; Piotrowska-Nowak et al. 2020. PubMed ID: 32740724). Some large cohort studies estimate the overall lifetime risk of vision loss among males with a pathogenic LHON variant as ~17-27%, and females with a pathogenic LHON variant as ~5-8% (Lopez Sanchez et al. 2021. PubMed ID: 34670133; Puomila et al. 2007. PubMed ID: 17406640). Previous estimates, however, were as high as ~50-60% in males and 10-20% in females (Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353).

Currently, there are no approved treatments for individuals with LHON, although research into effective drug or gene therapies is ongoing (Hage and Vignal-Clermont. 2021. PubMed ID: 34122299).

Genetics

LHON, a maternally-inherited disorder, is caused by pathogenic variants in the mitochondrial genome, with three specific missense variants accounting for ~90% of cases worldwide (Mackey et al. 1996. PubMed ID: 8755941; Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353): MT-ND1 m.3460G>A (p.Ala52Thr), MT-ND4 m.11778G>A (p.Arg340His), and MT-ND6 m.14484T>C (p.Met64Val). These three variants are located in three different genes that encode for subunits of the mitochondrial complex I (Kirches et al. 2011. PubMed ID: 21886454).

Clinical Sensitivity - Sanger Sequencing

Clinical sensitivity for this test is expected to be high as these three variants (MT-ND1 m.3460G>A (p.Ala52Thr), MT-ND4 m.11778G>A (p.Arg340His), and MT-ND6 m.14484T>C (p.Met64Val)) have been documented to account for ~90% of LHON cases worldwide (Mackey et al. 1996. PubMed ID: 8755941; Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353). The majority of LHON cases (~85%) have been shown to harbor a homoplasmic pathogenic variant that is stable across most tested tissues; however, heteroplasmic variants have been reported (Yu-Wai-Man et al. 2003. PubMed ID: 12518276; Phasukkijwatana et al. 2006. PubMed ID: 17072496).

Testing Strategy

Acceptable specimen types for this test are: whole blood, fresh/frozen tissue, or DNA extracted from whole blood or fresh/frozen tissue. 

This test utilizes long-range polymerase chain reaction followed by Sanger sequencing. To mitigate allele dropout, two separate PCR primer sets are used to amplify the entire mtDNA genome, resulting in two separate fragments for analysis. Only MT-ND1 m.3460G>A (p.Ala52Thr), MT-ND4 m.11778G>A (p.Arg340His), and MT-ND6 m.14484T>C (p.Met64Val) are included in this analysis. While the vast majority of these variants are identified as homoplasmic variants in affected individuals, heteroplasmic variation has been known to occur (Yu-Wai-Man et al. 2003. PubMed ID: 12518276; Phasukkijwatana et al. 2006. PubMed ID: 17072496). Due to technical limitations, variants <20% heteroplasmy may fall below the limit of detection for Sanger sequencing.

Human Genome Variation Society (HGVS) recommendations are used to name sequence variants (Human Genome Variation Society). mtDNA sequence variants are interpreted utilizing a combination of resources, including recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al. 2015. PubMed ID: 25741868), which was primarily developed for interpretation of variants in nuclear genes; as well as recommendations from the MSeqDR consortium (McCormick et al. 2020. PubMed ID: 32906214) and Baylor College of Medicine (Wong et al. 2020. PubMed ID: 31965079), which were developed specifically for mtDNA variant interpretation.

Indications for Test

Patients who present with features consistent with LHON or a family history of LHON are good candidates for this test.

Genes

Official Gene Symbol OMIM ID
MT-ND1 516000
MT-ND4 516003
MT-ND6 516006
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Related Test

Name
PGmito - Mitochondrial Genome Sequencing

Citations

  • Hage and Vignal-Clermont. 2021. PubMed ID: 34122299
  • Kirches et al. 2011. PubMed ID: 21886454
  • Kirkman et al. 2009. PubMed ID: 19525327
  • Lopez Sanchez et al. 2021. PubMed ID: 34670133
  • Mackey et al. 1996. PubMed ID: 8755941
  • Mascialino et al. 2012. PubMed ID: 21928272
  • McCormick et al. 2020. PubMed ID: 32906214
  • Moster et al. 2016. PubMed ID: 27459664
  • Phasukkijwatana et al. 2006. PubMed ID: 17072496
  • Piotrowska-Nowak et al. 2020. PubMed ID: 32740724
  • Puomila et al. 2007. PubMed ID: 17406640
  • Richards et al. 2015. PubMed ID: 25741868
  • Riordan-Eva et al. 1995. PubMed ID: 7735876
  • Wong et al. 2020. PubMed ID: 31965079
  • Yu-Wai-Man and Chinnery. 2021. PubMed ID: 20301353

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

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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.
Total Price: $
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