TFG-Related Disorders via the TFG 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
2857 TFG$910.00 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

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the TFG gene reported to date can be detected by sequencing.

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Clinical Features

The TFG gene has been associated with two different disorders: Okinawa hereditary motor and sensory neuropathy (HMSNO) and spastic paraplegia 57 (SPG57).

HMSNO is a neurodegenerative disorder originally found in patients living in Okinawa and Kansai in Japan. This disease is characterized by proximal muscle weakness and atrophy, muscle cramps, areflexia, fasciculations, and distal sensory loss (Maeda et al. 2007; Ishiura et al. 2012; Khani et al. 2016). It usually has adult onset ranging from 20 to 45 years (Patroclo et al. 2009; Lee et al. 2013; Tsai et al. 2014). HMSNO has clinical features in common with some other motor neuron disorders, such as spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT) and amyotrophic lateral sclerosis (ALS) (Maeda et al. 2007; Tsai et al. 2014; Khani et al. 2016). Therefore, molecular genetic testing is particularly useful for a precise diagnosis.

SPG57 is a type of hereditary spastic paraplegia (HSP) characterized by childhood-onset of progressive walking abnormalities and stiff legs (Beetz et al. 2013; Harlalka et al. 2016). In some patients with SPG57, the symptoms may be complicated by intellectual disability, optic atrophy, and neuropathy in the upper limbs (Beetz et al. 2013; Tariq et al. 2017).


TFG functions as octamers and plays important roles in the endoplasmic reticulum (ER) and the associated microtubules (Beetz et al. 2013; Kanadome et al. 2017). To date, in the TFG gene there are only 5 missense variants that have been reported to cause disease (Human Gene Mutation Database).

HMSNO is inherited in an autosomal dominant (AD) manner. Two missense variants (p.Pro285Leu and p.Gly269Val) each have been found to segregate in multiple families (Maeda et al. 2007; Ishiura et al. 2012; Lee et al. 2013; Tsai et al. 2014; Alavi et al. 2015). Functional studies showed that TFG with the p.Gly269Val substitution aggregated with wildtype TFG and impaired its function in a dominant negative manner (Tsai et al. 2014).

The inheritance pattern of SPG57 is autosomal recessive (AR). So far 3 missense pathogenic variants (p.Arg22Trp, p.Arg106Cys and p.Arg106His) have been identified in a homozygous state in patients with SPG57. Functional studies showed that TFG protein harboring these substitutions failed to assemble into an octamer and therefore impaired its function in ER organization (Beetz et al. 2013; Harlalka et al. 2016; Elsayed et al. 2016). Haplotyping analysis suggested that p.Arg106Cy might be a founder variant originating in India (Harlalka et al. 2016).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the TFG gene plus ~10 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known pathogenic variants or to confirm research results.

Indications for Test

Patients with AD motor and sensory neuropathy or AR spastic paraplegia are candidates for this test. Testing is also indicated for family members of patients who have known TFG pathogenic variants.


Official Gene Symbol OMIM ID
TFG 602498
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Complex Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection
Comprehensive Neuropathy Sequencing Panel
Hereditary Spastic Paraplegia Comprehensive Sequencing Panel with CNV Detection


Genetic Counselors
  • Alavi A. et al. 2015. Neurobiology of Aging. 36: 1606.e1-7. PubMed ID: 25725944
  • Beetz C. et al. 2013. Proceedings of the National Academy of Sciences of the United States of America. 110: 5091-6. PubMed ID: 23479643
  • Elsayed L.E. et al. 2016. European Journal of Human Genetics. 25: 100-110. PubMed ID: 27601211
  • Harlalka G.V. et al. 2016. Human Mutation. 37: 1157-1161. PubMed ID: 27492651
  • Human Gene Mutation Database (Bio-base).
  • Ishiura H. et al. 2012. American Journal of Human Genetics. 91: 320-9. PubMed ID: 22883144
  • Kanadome T. et al. 2017. The Febs Journal. 284: 56-76. PubMed ID: 27813252
  • Khani M. et al. 2016. Journal of the Neurological Sciences. 369: 318-23. PubMed ID: 27653917
  • Lee S.S. et al. 2013. Jama Neurology. 70: 607-15. PubMed ID: 23553329
  • Maeda K. et al. 2007. Journal of Human Genetics. 52: 907-14. PubMed ID: 17906970
  • Patroclo C.B. et al. 2009. Arquivos De Neuro-psiquiatria. 67: 892-6. PubMed ID: 19838524
  • Tariq H., Naz S. 2017. Neurogenetics. 18: 105-109. PubMed ID: 28124177
  • Tsai P.C. et al. 2014. Neurology. 83: 903-12. PubMed ID: 25098539
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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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