Peripheral Neuropathies via the HINT1 Gene

Pathogenic variants in the HINT1 gene cause inherited peripheral neuropathies that range from a strict distal motor neuropathy without sensory involvement to axonal neuropathy with neuromyotonia and mild sensory involvement (Zimon et al. 2012; Zhao et al. 2014). Therefore, some patients are clinically diagnosed as having Charcot Marie Tooth 2 whereas others are diagnosed with distal hereditary motor neuropathy. One defining clinical feature seen in many patients is neuromyotonia. In two different cohort studies around 70% of affected individuals had action myotonia in the hands and/or neuromyotonic discharges on needle EMG (Zimon et al. 2012; Laššuthová et al. 2015). Disease onset is typically in the first or second decade and most patients present with distal weakness in the lower and upper limbs; however, only lower limb involvement has also been observed. There is a predominance of more motor neuron involvement than sensory nerves being affected.

HINT1 peripheral neuropathies are inherited in an autosomal recessive manner. The HINT1 gene consists of 3 coding exons and encodes the 126 amino acid histidine triad nucleotide binding protein 1 (HINT1). HINT1 is a ubiquitously expressed homodimeric purine phosphoramidase and also acts as a tumor suppressor that functions in several apoptotic pathways (Zimon et al. 2012). Many of the pathogenic variants lie near the catalytic core and alter substrate binding, protein stability, or catalytic activity. Several of the described missense variants lie in the catalytic active site and abolish enzyme activity (Zimon et al. 2012). Reported pathogenic variants include missense and nonsense variants (Zimon et al. 2012, Zhao et al. 2014, Laššuthová et al. 2015). HINT1 is the fifth most frequent cause of CMT2/HMN in Czech populations with the p.Arg37Pro variant being the most common pathogenic variant in this population (Laššuthová et al. 2015). Carrier frequency of the P.Arg37Pro variant in Czech populations is estimated to be ~1:180 (Laššuthová et al. 2015).

In the original study describing HINT1 as a causative gene for inherited neuropathies, a large cohort study of individuals suspected of autosomal recessive inherited peripheral neuropathy was performed (Zimon et al. 2012). Thirty-one of 293 (11%) cases were found to have HINT1 pathogenic variants. In 31 patients specifically with axonal neuropathy and neuromyotonia, 21 (68%) were found to have HINT1 pathogenic variants. In an additional study using exome sequencing on patients with a clinical diagnosis of distal hereditary motor neuropathy, two of 12 were found to have HINT1 variants (Zhao et al. 2014). In another large cohort study of Czech patients with either motor neuropathy or motor and sensory neuropathy, 14 of 196 (7%) individuals had pathogenic HINT1 variants (Laššuthová et al. 2015). The estimated carrier frequency in Czech populations for the pathogenic Arg37Pro variant is estimated to be ~1:182. Analytical sensitivity should be almost 100% because all reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the HINT1 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).