Charcot-Marie-Tooth Disease and Distal Motor Neuropathy via the GBF1 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 muscles 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 regard to symptoms, severity and progression rate. Although the disease may lead to disability and respiratory difficulty, life expectancy is usually unaffected. The most common symptoms include foot deformity, loss of balance, hammertoes, foot drop, frequent tripping and falls, and reduced manual dexterity (Bird. 2021. PubMed ID: 20301532). Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction study (NCS) findings (Pareyson and Marchesi. 2009. PubMed ID: 19539237). CMT affects approximately 1 in 3,300 people (Bird. 2021. PubMed ID: 20301532).

GBF1-related neuropathies have been reported in four unrelated families to date (Mendoza-Ferreira et al. 2020. PubMed ID: 32937143). Clinical features include difficultly walking, foot deformities, foot drop, distal muscle weakness in upper and lower limbs, pes cavus deformity, mild sensory issues in some cases and NCS indicating axonal involvement. Age of onset ranged from mid-twenties to late fifties. Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in GBF1 are associated with autosomal dominant CMT2 or hereditary distal motor neuropathy (Mendoza-Ferreira et al. 2020. PubMed ID: 32937143). To date, only missense and one nonsense variant have been reported in the GBF1 gene in 4 unrelated families. In two patients, the variant was found to occur de novo and in the other two families the variant was inherited. In one case the variant was inherited from a presumably unaffected parent, indicating that reduced penetrance or variable expressivity may be possible. No structural variants have been reported.

GBF1 encodes Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 which facilitates GDP-to-GTP exchange for members of the ARF family of small GTPases. GBF1 is involved in maintenance and functioning of the Golgi apparatus and mitochondrial migration and positioning. Primary fibroblasts from affected individuals showed marked Golgi fragmentation. Early development studies in murine embryos indicate that GBF1 is present in neuronal tissues and cells necessary for motor neuron pathology (Mendoza-Ferreira et al. 2020. PubMed ID: 32937143). GBF1 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

The clinical sensitivity is difficult to estimate as to date only a limited number of cases have been described in the literature (Mendoza-Ferreira et al. 2020. PubMed ID: 32937143). Analytical sensitivity should be high as almost all pathogenic variants reported to date are detectable by sequencing. 

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the GBF1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).