Charcot-Marie-Tooth Type 2U via the MARS1/MARS Gene

Charcot Marie Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN) is a large group of inherited disorders of the peripheral nerves. The progressive degeneration of motor nerves results in weakness and atrophy of the distal muscles; and the degeneration of sensory nerves leads to decreased sensation, tingling and numbness in the legs, feet, arms and hands and neuropathic pain. The age of onset varies from childhood to mid adulthood. Symptoms usually begin with weakness and atrophy in the muscle of the legs and feet. As the disease progresses, weakness and atrophy of the muscles of the arms and hands may occur. CMT is heterogeneous in regards to symptoms, severity and progression rate. Although the disease may lead to disability and respiratory difficulty, life expectancy is usually unaffected. Most common symptoms include foot deformity, loss of balance, hammertoes, foot drop, frequent tripping and falls, and reduced manual dexterity. Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction velocity (NCV) findings (Pareyson and Marchesi 2009; Bird 2015). CMT affects approximately 1 in 3,300 people.

Charcot-Marie-Tooth type 2U (CMT2U) is an autosomal dominant form of CMT that is slowly progressive with late-adult onset. Patients present with bilateral foot drop, distal wasting in upper and lower limbs, mild distal weakness in upper limbs, and steppage gait (Hyun et al. 2014; Gonzalez et al. 2013).

Charcot-Marie-Tooth type 2U (CMT2U) is inherited in an autosomal dominant manner with reduced penetrance due to pathogenic variants in MARS1/MARS, located on chromosome 12q13.3. The MARS1 gene encodes the methionyl-tRNA synthetase protein which is an enzyme responsible for charging tRNA with corresponding amino acids. Variants of uncertain significance in MARS1 have also been reported in one patient with spastic paraplegia (Novarino et al. 2014). The variants p.Ser567Leu and p.Ala393Thr which reside on the same allele have been reported in the homozygous state in patients with interstitial lung and liver disease (Hadchouel et al. 2015). Thus far, only pathogenic missense variants in the MARS1 gene have been reported (Hyun et al. 2014; Gonzalez et al. 2013). 

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all reported pathogenic variants thus far are detectable by sequencing.

Thus far, no large deletions or duplications involving the MARS1 gene have been reported.

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