Charcot-Marie-Tooth Type 2R via the TRIM2 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, electromyography (EMG), and nerve conduction velocity (NCV) findings (Pareyson and Marchesi. 2009. PubMed ID: 19539237; Bird. 2015. PubMed ID: 20301532). CMT affects approximately 1 in 3,300 people.

Charcot-Marie-Tooth type 2R (CMT2R) is an autosomal recessive form of CMT that presents in infancy or early childhood. Two unrelated patients have been reported thus far with pathogenic variants in the TRIM2 gene. The first reported patient had an early-onset axonal neuropathy that presented with mild delay of motor development, hypotonia, atrophy of small muscles in the hands and feet, pes cavus, and a sural nerve biopsy with nonspecific axonal degeneration (Ylikallio et al. 2013. PubMed ID: 23562820). The second patient had a more severe phenotype with respiratory insufficiency associated with vocal cord paralysis, axial hypotonia, muscle weakness, knee contractures, pes equinus, pes cavus, and absent deep tendon reflexes. The EMG was consistent with a severe axonal polyneuropathy (Pehlivan et al. 2015. PubMed ID: 25893792).

Charcot-Marie-Tooth type 2R is inherited in an autosomal recessive manner due to pathogenic variants in TRIM2, located on chromosome 4q31.13. The TRIM2 gene encodes tripartite-motif containing protein 2 which functions as an E3 ubiquitin ligase. TRIM2 is a highly expressed protein in the nervous system that binds and regulates ubiquination of the neurofilament light subunit protein (Balastik et al. 2008. PubMed ID: 18687884). Thus far, reported pathogenic variants include missense variants and a small deletion that results in a frameshift and premature protein termination (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in TRIM2 appear to be a rare cause of disease. Analytical sensitivity should be high because almost all reported pathogenic variants thus far are detectable by sequencing.

Thus far, no large deletions or duplications involving the TRIM2 gene have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TRIM2 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).