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Autosomal Dominant Optic Atrophy with Cataract (ADOAC) and Costeff Syndrome or 3-Methylglutaconic Aciduria, Type III (MGA3) via the OPA3 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
OPA3 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7769OPA381479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

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

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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.


Genetic Counselors


  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Hereditary optic atrophies are a heterogeneous group of genetic disorders with different modes of inheritance. The most common forms are Autosomal Dominant Optic Atrophy (ADOA; OMIM# 165500) and Leber’s hereditary optic neuropathy (LHON, OMIM 535000). Both share a common pathological hallmark, the preferential loss of retinal ganglion cells (Yu-Wai-Man, P. et al. Ophthalmology 117(8):1538-1546, 2010). The OPA1 gene encodes a mitochondrial dynamin-like GTPase protein, and mutations in this gene have been implicated in 60-80% of ADOA cases (Reynier et al. J Med Genet 41(9): e110, 2004). Mutations in the OPA3 gene are responsible for ~3% of ADOA cases. These cases have been categorized a new clinical entity called ADOA with cataract (ADOAC; OMIM# 165300) (Reynier, et al., 2004; Ferre, M. et al. Hum Mutat 30(7): E692-705, 2009). ADOAC is characterized by optic atrophy with cataract that occurs in the early teenage years in association with milder extrapyramidal signs and ataxia (Reynier, et al. 2004; Ayrignac et al. Eur Neurol 68(2):108-110, 2012).

OPA3 was originally identified as the gene mutated in autosomal recessive 3-methylglutaconic aciduria, type III (MGA3 or Costeff optic atrophy syndrome; OMIM#258501). MGA3 is one of five MGA syndromes characterized by optic atrophy associated with progressive, reduced visual acuity and/or choreoathetoid (irregular migrating contractions, twisting and writhing) movement disorder. MGA3 has onset before age ten years and is sometimes associated with infantile-onset horizontal nystagmus. About half of the patients develop spastic paraparesis, milder ataxia, and occasional mild cognitive deficit in their second decade of life (Costeff et al. Neurology 39(4): 595-597, 1989). Abnormal urinary excretion of 3-methyl glutaconic acid (3-MGA) and high plasma 3-methylglutaric acid levels are the pathological hallmark of MGA3. It is recommended that patients with early optic atrophy, and especially those with motor dysfunction, should be tested for this organic aciduria (Costeff, H., et al. Ann Neurol 33(1):103-104, 1993; Gunay-Aygun, M. et al. GeneReviews, 2009). The estimated prevalence rate of Costeff syndrome caused by the OPA3 founder mutation is about 1:10,000 in the Iraqi Jewish community in Israel (Costeff, H. et al., 1989), with a carrier frequency of ~1 in 10 (Anikster, Y. Am J Hum Genet 69(6):1218-1224).


ADOA is genetically heterogeneous. Linkage analysis of large multi-generational pedigrees has revealed five distinct autosomal loci (OPA1, OPA3, OPA4, OPA5, and OPA7), but to date, only the causative genes for OPA1 (3q28-q29) and OPA3 (19q13.2-q13.3) have been identified (Yu-Wai-Man et al, 2010). OPA1 (OMIM 605290) and OPA3 (OMIM 606580) both encode mitochondrial proteins that share the same mitochondrial inner membrane location, and are jointly involved in the regulation of mitochondrial oxidative phosphorylation, network maintenance, and the sequestration of pro-apoptotic cytochrome c oxidase molecules within the cristae spaces (Ferre et al., 2009; Yu-Wai-Man et al., 2010).

A study on a Costeff Syndrome model (zebrafish) has shown that the OPA3 mRNA is expressed in the optic nerve and photoreceptors, the counterparts that are marked by high mitochondrial activity in humans, suggesting that the transcription and intracellular distribution of OPA3 is regulated to meet mitochondrial demand. It has also been observed that the exogenous delivery of OPA3 can reduce abnormal MGA levels in OPA3 mutants and protect the electron transport chain against toxic compounds (Pei et al. Development 137(15):2587-2596, 2010). Patients homozygous for OPA3 mutations with loss of function display a severe multi-systemic disease with optic atrophy, whereas a heterozygous missense mutation results in a milder phenotype. To date, only five mutations that include missense/nonsense, splice site, and a small deletion have been identified in OPA3. Reynier et al. (2004) reported 2 dominant heterozygous mutations (c.277 G>A and c.313 C>G) in exon 2 of OPA3 in patients with ADOAC, which segregated with the disease in each family and were absent in healthy relatives and in 400 control chromosomes. There were no abnormalities in the mitochondria of the fibroblasts obtained from one affected patient, but the fibroblasts showed increased susceptibility to apoptosis (Reynier et al., 2004). The prevalent G→C splice-site mutation (IVS1-1G>C) in OPA3 segregated with MGA3 in Iraqi Jewish families and accounts for 100% of disease-causing alleles in this population, indicating a founder effect (Anikster et al., 2001). The mutations that were found to date in individuals of non-Iraqi Jewish origin are inframe deletion (c.320-337del) in a Kurdish-Turkish patient with optic atrophy and MGA3 (Kleta, R. et al. Mol Genet Metab 76(3):201-206,2002) and c.415C>T (p. Q139X) in a homozygous state in an individual of Indian origin with MGA3 (Ho, G. et al. J Inherit Metab Dis 31 Supple 2:S419-423, 2008).

Clinical Sensitivity - Sequencing with CNV PG-Select

Molecular screening of 980 suspected hereditary optic neuropathy patients identified OPA1 mutations in 45% of patients (440) and OPA3 in 3% (14) of patients belonging to 3 unrelated families (Ferre, M. Hum Mutat 30(7): E692-705, 2009). In a different study of 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 OPA3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Ideal OPA3 test candidates are ADOAC, MGA3 patients and patients undergoing a diagnostic evaluation of suspected hereditary optic neuropathy or have a family history of optic neuropathy. Testing should begin with an affected family member. It is recommended that in the familial cases, OPA1 be tested first whenever an autosomal dominant inheritance is obvious. All negative OPA1 cases should be subsequently analyzed by the sequencing of OPA3 coding regions (Ferre, M. et al, 2009). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in OPA3.


Official Gene Symbol OMIM ID
OPA3 606580
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Mitochondrial Genome Maintenance/Integrity Nuclear Genes Panel
Optic Atrophy Panel


  • Anikster, Y. et al. (2001). “Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews.” Am J Hum Genet 69(6):1218-24. PubMed ID: 11668429
  • Ayrignac, X. et al. (2012). “OPA3--related autosomal dominant optic atrophy and cataract with ataxia and areflexia.” Eur Neurol 68(2):108-110. PubMed ID: 22797356
  • Costeff, H. et al. (1993). “3-Methylglutaconic aciduria in "optic atrophy plus".” Ann Neurol 33(1):103-104. PubMed ID: 8494328
  • Costeff, H. et al. (1989). "A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia." Neurology 39(4): 595-597. PubMed ID: 2494568
  • Ferrι 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
  • Gunay-Aygun, M et al. (2009). "3 Methylglutaconic Aciduria Type 3" GeneReviews. PubMed ID: 20301646
  • Ho, G., et al. (2008). "Costeff optic atrophy syndrome: new clinical case and novel molecular findings." J Inherit Metab Dis 31 Suppl 2:S419-423. PubMed ID: 18985435
  • Kleta, R., et al. (2002). “3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings.”  Mol Genet Metab 76(3):201-6. PubMed ID: 12126933
  • 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
  • Pei, W., et al. (2010). “A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3Development 1;137(15):2587-96. PubMed ID: 20627962
  • Reynier, P. et al. (2004). "OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract." J Med Genet  41(9): e110. PubMed ID: 15342707
  • 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


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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

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