Charcot-Marie-Tooth Autosomal Dominant Intermediate F via the GNB4 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. 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.

Dominant intermediate Charcot-Marie-Tooth type F is characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. Individuals in the originally reported families exhibited a motor and sensory neuropathy with onset between age 5 and 45 years, distal leg weakness and atrophy, high-arched feet, and hammer toes (Soong et al. 2013; Laššuthová et al. 2017). At least two individuals showed a primary demyelingating neuropathy with secondary axonal loss and ongoing denervation on EMG.

Dominant intermediate Charcot-Marie-Tooth type F is inherited in an autosomal dominant manner due to pathogenic variants in GNB4, located on chromosome 3q26.33. The GNB4 gene encodes the guanine-nucleotide-binding protein subunit beta-4 (Gβ₄) which is part of a heterotrimeric G protein which is important in cellular signal transduction. Gβ₄ colocalized with neurofilament heavy chain and S100, indicating that Gβ₄ is expressed in both axons and schwann cells (Soong et al. 2013). Thus far, only pathogenic missense variants in GNB4 gene have been reported and many times occur de novo (Human Gene Mutation Database; Soong et al. 2013; Laššuthová et al. 2017).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in GNB4 appear to be a rare cause of disease. 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 GNB4 gene have been reported.

This test provides full coverage of all coding exons of the GNB4 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).