TSFM-Related Combined Oxidative Phosphorylation Deficiency via the TSFM Gene
- Summary and Pricing
- Clinical Features and Genetics
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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).
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).
Indications for Test
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- Genetic Counselor Team - email@example.com
- Kym Bliven, PhD - firstname.lastname@example.org
- 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
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). 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.
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).
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.
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