Charcot-Marie-Tooth 1C via the LITAF 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 1C (CMT1C) is a demyelinating form of CMT that primarily affects the myelin sheath of the peripheral nerve. Patients with CMT1C will exhibit the typical slow nerve conduction velocities (NCV) of a demyelinating neuropathy, distal muscle weakness and atrophy, depressed deep tendon reflexes, and sensory impairment. Onset is typically in the 30-50s, but early onset in the first decade has also been reported (Ciotti et al. 2014).

Charcot-Marie-Tooth type 1C (CMT1C) is inherited in an autosomal dominant manner due to pathogenic variants in LITAF, located on chromosome 16p13.13. The LITAF gene encodes the lipopolysaccharide-induced TNF-α factor (LITAF) protein which is involved in cytokine signaling and tumor suppression; however, the exact cellular role is not fully understood. Thus far, all reported pathogenic variants have been missense variants (Human Gene Mutation Database; Ciotti et al. 2014; Street et al. 2003).

A genetic etiology can be identified in approximately 50-70% of individuals with Charcot-Marie-Tooth (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). CMT1A (70%-80% of all CMT1) involves duplication of the PMP22 gene. CMT1B (6%-10% of all CMT1) is associated with single-nucleotide variants in MPZ (Bird 2015). CMT1C (1%-2% of all CMT1) is associated with pathogenic variants in LITAF, and CMT1D (<2% of all CMT1) is associated with pathogenic variants in EGR2.

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

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