TFG-Related Disorders via the TFG Gene

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).

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.

This test provides full coverage of all coding exons of the TFG gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).