Charcot-Marie-Tooth Type 4B3 via the SBF1 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 4B3 (CMT4B3) and/or pathogenic variants in SBF1 have been reported in at least four unrelated families, with variable presentation (Alazami et al., 2014. PubMed ID: 24799518; Nakhro et al., 2013. PubMed ID: 23749797; Romani et al., 2016. PubMed ID: 27123480). In the originally described Korean family, three affected siblings presented with a homogenous phenotype of pure sensory motor demyelinating neuropathy with focally folded myelin sheaths (Nakhro et al., 2013. PubMed ID: 23749797). In the second described SBF1 family, three affected siblings presented with a more complex phenotype of sensory motor polyneuropathy with microcephaly, intellectual disability, syndactyly, and cranial nerve involvement (Alazami et al., 2014. PubMed ID: 24799518). A more recent report described a third family with two affected siblings who presented with progressive microcephaly, multiple cranial nerve neuropathies, and moderate to severe intellectual disability (Romani et al., 2016. PubMed ID: 27123480). These individuals presented with an axonal sensory motor neuropathy with evidence of denervation.

Charcot-Marie-Tooth type 4B3 (CMT4B3) is inherited in an autosomal recessive manner due to pathogenic variants in SBF1, located on chromosome 22q13.33. The SBF1 gene encodes myotubularin-related protein 5 also called set-binding factor 1. The SBF1 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 variants and a small deletion that results in a frameshift (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in SBF1 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 SBF1 gene have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SBF1 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).