Autosomal Dominant Progressive External Ophthalmoplegia and Hypertrophic Cardiomyopathy with Mitochondrial Myopathy via the SLC25A4 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1250 SLC25A4$580.00 81404 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

SLC25A4 defects accounted for approximately 4% of familial adPEO cases in one Italian cohort (Lamantea et al. 2002). The clinical sensitivity for SLC25A4-associated hypertrophic cardiomyopathy with mitochondrial myopathy is difficult to estimate at this time, as pathogenic variants have been reported in fewer than 20 individuals (Echaniz-Laguna et al. 2012; Körver-Keularts et al. 2015; Palmieri et al. 2005; Strauss et al. 2013). 

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC25A4$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

No gross deletions or insertions have been reported in the SLC25A4 gene to date (Human Gene Mutation Database).

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Clinical Features

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder characterized by progressive external ophthalmoplegia and ptosis, with multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle (Chinnery 2014; Kaukonen et al. 2000). SLC25A4-associated adPEO is an adult-onset disease. Patients may not develop generalized muscle weakness until the fifth decade of life (Kaukonen et al. 2000; Komaki et al. 2002). To date, only a few SLC25A4-linked adPEO families have been reported worldwide (Kaukonen et al. 2000; Komaki et al. 2002; Park et al. 2011).

Hypertrophic cardiomyopathy with mitochondrial myopathy is another SLC25A4-related disorder (Palmieri et al. 2005; Echaniz-Laguna et al. 2012; Strauss et al. 2013). This adult-onset, autosomal recessive disease is characterized by hypertrophic cardiomyopathy, myopathy with exercise intolerance, lactic acidosis, and multiple mtDNA deletions. Ophthalmoplegia is notably absent in these patients, although one patient with complete loss of the SLC25A4 transcript presented with congenital cataracts (Echaniz-Laguna et al. 2012). Significant clinical variability may exist among family members with this disorder, which might be linked to differences in mitochondrial DNA (mtDNA) haplogroups (Strauss et al. 2013).


SLC25A4 defects are a rare cause of adult-onset, autosomal dominant progressive external ophthalmoplegia (PEO) (Kaukonen et al. 2000; Fratter et al. 2010). In contrast, SLC25A4-related hypertrophic cardiomyopathy with mitochondrial myopathy is inherited in an autosomal recessive manner (Echaniz-Laguna et al. 2012; Körver-Keularts et al. 2015; Strauss et al. 2013). 

SLC25A4, commonly referred to as ANT1, has 4 exons and encodes for the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1), an ATP/ADP translocator that is thought to play a key role in mtDNA maintenance (Kaukonen et al. 2000). Pathogenic SLC25A4 variants include missense mutations (the majority), two small frameshifting deletions, and one splicing variant (Human Gene Mutation Database).

Defects in C10orf2, POLG, POLG2, RRM2B, and DNA2 may also cause adPEO (Fratter et al. 2010; Ronchi et al. 2013).

Testing Strategy

Full gene sequencing of SLC25A4 is performed, with bidirectional sequencing of the 4 coding exons of the SLC25A4 gene. The entire coding region of each exon plus ~20 bp of flanking non-coding DNA on either side are sequenced. 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

Candidates for this test include patients with adPEO, particularly when sequencing of the C10orf2, POLG, POLG2 and RRM2B genes has not revealed any probable causative variants. Candidates for this test may also include patients affected by hypertrophic cardiomyopathy with mitochondrial myopathy. Finally, testing is indicated for family members of patients who have known pathogenic variants in SLC25A4.


Official Gene Symbol OMIM ID
SLC25A4 103220
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

POLG-Related Mitochondrial Disorders via the POLG Gene
RRM2B-Related Mitochondrial Disorders via the RRM2B Gene
Autosomal Dominant Progressive External Ophthalmoplegia and other C10orf2-related disorders via the TWNK/C10orf2 Gene
Autosomal Dominant Progressive External Ophthalmoplegia via the DNA2 Gene
Autosomal Dominant Progressive External Ophthalmoplegia via the POLG2 Gene
Mitochondrial Genome Maintenance/Integrity Nuclear Genes Sequencing Panel


Genetic Counselors
  • Chinnery P.F. 2014. Mitochondrial Disorders Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301403
  • Echaniz-Laguna A. et al. 2012. Journal of Medical Genetics. 49:146-50. PubMed ID: 22187496
  • Fratter C. et al. 2010. Neurology. 74:1619-26. PubMed ID: 20479361
  • Human Gene Mutation Database (Bio-base).
  • Kaukonen J. et al. 2000. Science. 289:782-5. PubMed ID: 10926541
  • Körver-Keularts I.M. et al. 2015. JIMD Reports. 22:39-45. PubMed ID: 25732997
  • Komaki H. et al. 2002. Annals of Neurology. 51:625-8. PubMed ID: 12112115
  • Lamantea E. et al. 2002. Annals of Neurology. 52:211-9. PubMed ID: 12210792
  • Palmieri L. et al. 2005. Human Molecular Genetics. 14:3079-88. PubMed ID: 16155110
  • Park K.P. et al. 2011. Journal of Clinical Neurology. 7:25-30. PubMed ID: 21519523
  • Ronchi D. et al. 2013. American Journal of Human Genetics. 92:293-300. PubMed ID: 23352259
  • Strauss K.A. et al. 2013. Proceedings of the National Academy of Sciences of the United States of America. 110:3453-8. PubMed ID: 23401503
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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 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 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 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

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 20 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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