Charcot-Marie-Tooth Type 4B2 via the SBF2 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 4B2 (CMT4B2) is a demyelinating form of CMT that primarily affects the myelin sheath of the peripheral nerve. Patients with CMT4B2 will exhibit the typical slow nerve conduction velocities (NCV) of a demyelinating neuropathy, distal muscle weakness and atrophy, depressed deep tendon reflexes, foot deformities such as hammertoes and pes cavus, and sensory impairment (Azzedine et al., 2003. PubMed ID: 12687498; Hirano et al., 2004. PubMed ID: 15304601). Sural nerve biopsy will show myelin outfoldings, which are a hallmark of CMT4B. Of note, some cases have also presented with early onset glaucoma (Hirano et al., 2004. PubMed ID: 15304601; Chen et al., 2014. PubMed ID: 25462154). The onset is typically in the first to second decade of life.

Charcot-Marie-Tooth type 4B2 (CMT4B2) is inherited in an autosomal recessive manner due to pathogenic variants in SBF2, located on chromosome 11p15.4. The SBF2 gene encodes myotubularin-related protein 13 also called set-binding factor 2. The SBF2 protein has been shown to interact with MTMR2 and regulates the enzymatic activity; however, the exact cellular role is not fully understood. Thus far, reported pathogenic variants include missense, nonsense, splicing and small deletions that result 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 SBF2 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, only two large deletions involving the SBF2 gene have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SBF2 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).