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Autosomal Dominant Optic Atrophy (ADOA) or Optic Atrophy, Kjer-Type (OAK) and DOA Plus Syndrome (DOA+) via the OPA1 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
11543 OPA1 81407 81407,81406 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11543OPA181407 81407,81406 $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

Autosomal Dominant Optic Atrophy (ADOA; OMIM# 165500) 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, V., et al. Biochim Biophys Acta 1787(5):518–528, 2009; Yu-Wai-Man, P., et al. Ophthalmology. 117(8):1538-1546, 2010). ADOA is clinically characterized by bilateral reduction in visual acuity that progresses insidiously from early childhood onwards (Yu-Wai-Man, P., et al. Ophthalmology. 118(3):558-563, 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. However, there is a marked inter-and intrafamilial variation in disease severity (Votruba, M., et al. Hum. Genet. 102(1): 79-86, 1998). Phenotype-genotype studies of optic atrophies found that 20% of DOA patients develop a more severe phenotype called “DOA plus” (DOA+, OMIM# 125250), 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, P., et al. 2010; Amati-Bonneau, P. et al. Int J Biochem Cell Biol 41(10):1855-1865, 2009). Disease prevalence is estimated as 3/100,000 in most populations in the world, but in Denmark it can reach to 1/10,000 due to a founder effect (Kjer, B. et al. Acta Ophthalmol Scand 74(1):3-7, 1996; Thiselton, DL. et al. Hum Genet 109(5):498-502, 2001).

Genetics

Although heterogeneous, the majority of suspected hereditary optic neuropathy patients (>60%) harbor pathogenic mutations within OPA1; ~30% have mtDNA mutations; and ~3% have OPA3 mutations (Ferre et al. Hum Mutat 30(7): E692-705, 2009). OPA1 encodes mitochondrial dynamin-like GTPase, which localizes to the inner mitochondrial membrane and regulates several important cellular processes, which include the stability of the mitochondrial network, mitochondrial bioenergetic output, sequestration of proapoptotic cytochrome C oxidase molecules within the mitochondrial cristae spaces, control of apoptosis, maintenance of mitochondrial DNA and oxidative phosphorylation (Ferre et al., 2009; Yu-Wai-Man et al., 2010). OPA1 is composed of 30 coding exons that span ~90 kb of genomic DNA on chromosome 3q28-q29. Alternative splicing of exons 4, 4b, 5 and 5b leads to eight transcript isoforms shown to be expressed in a variety of tissues (Alavi, M.V. et al. Brain 130(Pt 4):1029-1042, 2007). Almost 50% of OPA1 mutations lead to haploinsufficiency due to complete deletion of the gene and nonsense mediated mRNA decay, which is believed to be the major pathomechanism underlying OPA1-associated ADOA (Pesch, U.E. et al. Hum Mol Genet 10(13):1359-1368, 2001). OPA1 genomic rearrangements account for ~13% cases of ADOA, suggesting that deletion and duplication analysis should be included in the routine genetic analysis of ADOA patients (Marchbank, N.J. et al. J Med Genet 39(8): e47, 2002 ; Fuhrmann, N. et al. J Med Genet 46(2):136-144, 2009 ; Almind, G.J. et al. BMC Med Genet 12:49, 2011). The haploinsufficiency has been shown to affect retinal ganglion cells, which have many mitochondria and especially high energy requirement due to their non-myelinated specialized extensions called axons that form the optic nerve. Based on Fuhrmann et al. (2009) genotyping results, ADOA penetrance was ~88%, which is consistent with previous reports (Toomes, C. et al. Hum Mol Genet 10(13):1369-1378, 2001; Cohn, A.C. et al. Am J Ophthalmol 143(4):656-662, 2007). Missense, nonsense, insertions, deletions and splicing mutations have been reported within OPA1 and are spread throughout the coding region, with most of them clustering over the cDNA region corresponding to the GTPase domain (Exons 8-16) and the 3' end of the coding region (exon 27-28) (Pesch, U.E. et al. 2001; Toomes, C. et al., 2001).

Clinical Sensitivity - Sequencing with CNV PGxome

In a molecular screening of 980 cases of suspected hereditary optic neuropathy, 440 patients had molecular defects. Among these 440 patients, 295 had OPA1 mutations (67%) 131 patients had (30%) mtDNA mutations, and 14 patients (3%) had OPA3 mutations (Ferre, M., et al. Hum Mutat 30(7):E692-705, 2009). In another study done with ADOA patients, 75% of the cases had OPA1 mutations, whereas 1% of patients had OPA3 mutations (Lenaers, G. et al. Orphanet J Rare Dis 7:46, 2012).

Testing Strategy

This test provides full coverage of all coding exons of the OPA1 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

Ideal OPA1 test candidates are ADOA, DOA+ patients and patients undergoing a diagnostic evaluation of suspected hereditary optic neuropathy or a family history of optic neuropathy. Testing should begin with an affected family member. In the familial cases, OPA1 should be tested first, whenever autosomal dominant inheritance is obvious. If no OPA1 mutation is found, OPA3 should be considered.

Gene

Official Gene Symbol OMIM ID
OPA1 605290
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Dominant Hereditary Optic Atrophy AD 165500
Optic Atrophy Type 1 AD 125250

Citations

  • Alavi, M.V. et al. (2007). PubMed ID: 17314202
  • Almind GJ, Grønskov K, Milea D, Larsen M, Brøndum-Nielsen K, Ek J. 2011. Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy. BMC medical genetics 12: 49. PubMed ID: 21457585
  • 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
  • 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
  • Cohn, A.C. et al. (2007). PubMed ID: 17306754
  • 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
  • Fuhrmann, N. et al. (2009). PubMed ID: 19181907
  • 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
  • Marchbank, N.J. etal. (2002). PubMed ID: 12161614
  • Pesch, U.E. et al. (2001). PubMed ID: 11440988
  • 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
  • Toomes, C. et al. (2001). PubMed ID: 11440989
  • Votruba, M. et al. (1998). PubMed ID: 9490303
  • 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)


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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