Charcot-Marie-Tooth Type 2E/1F via the NEFL 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.

Pathogenic variants in the NEFL gene can result in CMT neuropathies with variable clinical and electrophysiological expression. Many patients have been reported with an early disease onset and are usually more severely affected (Jordanova 2003; Sivera et al. 2013).

Charcot-Marie-Tooth type 2E/1F is inherited in both an autosomal dominant and autosomal recessive manner due to pathogenic variants in NEFL, located on chromosome 8p21. The NEFL gene encodes the neurofilament light chain polypeptide (NEFL) which is one of the most abundant cytoskeletal components of the neuron. Genetic defects of NEFL found to date include missense, nonsense, and small deletions/insertions (Human Gene Mutation Database). In one study, a genotype/phenotype correlation of NEFL pathogenic variants could not be identified. However, the authors suggested that pathogenic variants in the NEFL protein head domain can cause more severe motor and sensory NCV slowing than pathogenic variants in the coil 2B domain (Miltenberger-Miltenyi et al. 2007). Autosomal dominant inheritance is most commonly reported; however, a few recessive cases have been reported (Yum et al. 2009, Abe et al. 2009). The recessive cases do not always exhibit a more severe phenotype (Abe et al. 2009).

A genetic etiology can be identified in approximately 50-70% of individuals with CMT (Saporta et al. 2011; Rossor et al. 2013). Specifically, a molecular diagnosis can be identified in approximately 80-85% of individuals with demyelinating neuropathy (CMT1). CMT2E/1F (<5% of all CMT1) is associated with pathogenic variants in NEFL (Bird 2015). In one study of 323 patients with different CMT phenotypes, 2% of cases were found to have a pathogenic NEFL variant (Jordanova 2003).

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

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