Charcot-Marie-Tooth Type 4J via the FIG4 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. Lancet Neurol 8:654-67, 2009). CMT affects approximately 1 in 3,300 people.

CMT is genetically heterogeneous. Five distinct groups are recognized based on the mode of inheritance and the primary pathological defect (De Jonghe. J Peripher Nerv Syst 2:370-87, 1997). A small fraction of CMT patients are isolated cases caused by de novo mutations. CMT4 is inherited with in autosomal recessive fashion and is usually more severe than other forms. It may present as either a myelinopathy or axonopathy. CMT4J is caused by defects in the FIG4 gene. To date, approximately 20 different FIG4 causative mutations were reported in patients with variable clinical features and severity (Chow et al. Nature 448:68-72, 2007; Nicholson et al. Brain 134:1959-71, 2011). FIG4 mutations are distributed along the entire coding region of the gene. With the exception of three missense mutations and one large genomic deletion, all mutations are predicted to result in truncated proteins and include nonsense, splicing, small deletion, insertions, and indels. FIG4 encodes an inositol phospholipid phosphatase that is involved in the formation of melanosomes and neurosecretory granules.

Unknown at this time.

This test provides full coverage of all coding exons of the FIG4 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).