Giant Axonal Neuropathy via the GAN Gene

Giant axonal neuropathy (OMIM 256850) is a slowly progressive neurodegenerative disorder of childhood onset affecting both the peripheral and central nervous systems. Mean age of onset among multiple affected families was reported to be 6-10 years of age and 2-7 years of age (Zemmouri et al. Neuromusc Disord 10:592- 598, 2000; Tazir et al. Neuromusc Disorder 19:270-274, 2009). The presenting clinical sign is often an unsteady gait in a child who began walking late. Peripheral motor and sensory neuropathy affects the lower limbs more than the upper limbs, and weakness tends to be diffuse. MRI detects cerebellar atrophy later in the course of the disease (Zemmouri et al. Neuromusc Disord 10:592-598, 2000). Motor nerve conduction velocities are normal or mildly reduced. Nerve biopsies in affected patients reveal axonal loss and the presence of giant axonal swellings filled with neurofilaments (Nalini et al. Eur J Med Genet 51:426-435, 2008). Other clinical features include characteristic kinky hair, long and curly eyelashes, variable degree of mental retardation, and seizures (Kuhlenbäumer and Timmerman. GeneReviews 2009).

Gigaxonin is present in the cytoskeleton and is essential for neuronal function and survival because of its interaction with ubiquitin-activating enzyme E1and subsequent involvement in protein degradation (Allen et al. Nature 438:224-228, 2005). Giant cell neuropathy is inherited as an autosomal recessive disorder (Bomont et al. Nature Genet 26:370-374, 2000). The largest class of pathogenic GAN gene variants is missense and nonsense variants. Splice site variants, small insertions and deletions, and gross deletions and insertions are also reported.

Clinical sensitivity should be high in patients meeting clinical and histological criteria for this disorder. Analytical sensitivity is predicted to be less than 100% because gross copy number variants of the GAN gene are known.

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