TSFM-Related Combined Oxidative Phosphorylation Deficiency via the TSFM Gene

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  • Clinical Features and Genetics
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  • Methods
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
2985 TSFM$780.00 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
TSFM-associated combined oxidative phosphorylation (OXPHOS) deficiency has been described in fewer than 10 individuals to date (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Although we cannot precisely estimate clinical sensitivity at this time, pathogenic variants in TSFM appear to be a rare cause of combined OXPHOS deficiency.

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Clinical Features
Combined oxidative phosphorylation (OXPHOS) deficiency is a multi-systemic disorder characterized by reduced activity of two or more mitochondrial respiratory chain enzyme complexes. Pathogenic variants in over 30 different genes, primarily mitochondrial translation factors, have been linked to this disease. 

TSFM-associated combined OXPHOS deficiency exhibits significant clinical heterogeneity. Patients may present with infantile encephalopathy, hypertrophic cardiomyopathy, early onset hepatic failure, and/or Leigh syndrome, a subacute necrotizing encephalopathy characterized by brain stem or basal ganglia involvement, lactic acidosis, and progressive neurologic disease (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Despite this broad spectrum of possible clinical manifestations, all patients share distinctive biochemical abnormalities such as severe lactic acidosis and multiple respiratory complex deficiencies. Optic neuropathy, dystonia, ataxia, epilepsy, and cognitive impairment have also been occasionally reported in individuals with this disorder (Ahola et al. 2014; Smeitink et al. 2006).

Symptomatic onset of TSFM-associated combined OXPHOS deficiency usually occurs at birth or within the first year, although at least one affected individual first presented at the age of fifteen years (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Due to the severe complications associated with this disease and a lack of treatment options, half of all reported patients died within the first two months following birth (Smeitink et al. 2012; Vedrenne et al. 2012). Individuals that survived into adulthood generally presented later in life with milder symptoms (Ahola et al. 2014).
Combined oxidative phosphorylation (OXPHOS) deficiency is an autosomal recessive, X-linked, or maternally inherited disease. Pathogenic variants in over 30 different nuclear and mitochondrial genes have been reported as causative for this disorder. The majority of these genes encode for elements of the mitochondrial translation apparatus or mitochondrial tRNAs or rRNAs. 

Nuclear genes associated with autosomal recessive inheritance of combined OXPHOS deficiency include: AARS2, ATP5A1, BOLA3, C12orf65, EARS2, ELAC2, FARS2, GFER, GFM1, GTPBP3, ISCU, LYRM4, MARS2, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, NARS2, NFU1, PARS2, PNPT1, PUS1, RMND1, SERAC1, SFXN4, TARS2, TRMT5, TSFM, TUFM, VARS2, and YARS2.

AIFM1 is the only gene associated with X-linked recessive inheritance of this disease.

Additionally, pathogenic defects in any of the mitochondrial-encoded tRNA genes (22 total) or rRNA genes (2 total) are expected to result in combined oxidative phosphorylation deficiency (Smits et al. 2010).

The nuclear TSFM gene encodes for the mitochondrial translation elongation factor S, which binds the EF-Tu:GDP complex during protein biosynthesis to facilitate the exchange of GDP for GTP (Akama et al. 2010). To date, one nonsense and two missense changes have been reported for TSFM-related combined oxidative phosphorylation deficiency (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). The pathogenic c.856C<T (p.Gln286*) variant is carried at an extremely high frequency (1:80) in Finnish populations; however, this variant has only been detected in compound heterozygotes or carriers (Ahola et al. 2014; Lim et al. 2014). No homozygotes were detected in a population study of over 35,000 Finns, indicating that the c.856C<T (p.Gln286*) variant is most likely lethal in the homozygous state during embryonic development (Lim et al. 2014).
Testing Strategy
Full gene sequencing of TSFM is performed, with bidirectional sequencing of exons 1-7. The full coding region of each exon plus ~10 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
TSFM sequencing should be considered in patients with a family history of combined oxidative phosphorylation deficiency, or patients who present with symptoms consistent with this disorder.  We will also sequence the TSFM gene to determine carrier status.


Official Gene Symbol OMIM ID
TSFM 604723
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Combined Oxidative Phosphorylation Deficiency 3 610505


Genetic Counselors
  • Ahola S. et al. 2014. Neurology. 83: 743-51. PubMed ID: 25037205
  • Akama K. et al. 2010. Biochimica Et Biophysica Acta. 1802: 692-8. PubMed ID: 20435138
  • Lim E.T. et al. 2014. Plos Genetics. 10: e1004494. PubMed ID: 25078778
  • Smeitink J.A. et al. 2006. American Journal of Human Genetics. 79: 869-77. PubMed ID: 17033963
  • Smits P. et al. 2010. Journal of Biomedicine & Biotechnology. 2010: 737385. PubMed ID: 20396601
  • Vedrenne V. et al. 2012. Journal of Hepatology. 56: 294-7. PubMed ID: 21741925
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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.

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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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