Autosomal Dominant Optic atrophy with cataract (ADOAC) and Costeff Syndrome or 3-methylglutaconic aciduria, type III (MGA3) via the OPA3 Gene

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  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
567 OPA3$490.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 OPA3$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

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).

Testing Strategy

Full gene sequencing of OPA3 involves bidirectional Sanger sequencing of 2 exons plus ~10 bp additional flanking intronic or other non-coding sequence.  We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

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).


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


Genetic Counselors
  • 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
  • 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
  • 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 OPA3.” Development 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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