Glycyl tRNA Synthetase-Related Disorders via the GARS1/GARS Gene

Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472) and distal hereditary motor neuronopathy type V (HMNV; OMIM 600794) represent a phenotypic continuum of distal neuropathy with weakness and wasting starting in the distal limbs, predominately the hands. Distal sensory loss is evident in CMT2D, while in HMNV it is not, thus differentiating the two disorders (Irobi et al. Hum Mol Genet 13:195-202, 2004; Sivakumar et al. Brain 128:2304-2314, 2005). Onset is usually between childhood and young adulthood and progression is slow. Early signs in many patients are transient cramping and pain in the hands after exposure to cold, and cramping in calf muscles following exertion (Goldfarb and Sivakumar GeneReviews, 2007). Denervation is evident by electromyography, although sensory motor nerve conduction potentials are normal (Ionasescu et al. Hum Mol Genet 5:1373-1375, 1996; Sivakumar et al. 2005).

Charcot-Marie-Tooth disease, type 2D and distal hereditary motor neuronopathy, type V are inherited as autosomal dominant disorders. Variants in the gene encoding glycyl tRNA synthetase (GARS1/GARS; OMIM 600287) are the cause of both neuropathies (Antonellis et al. Am J Hum Genet 72:1293-1299, 2003). Variation in phenotypic expression exists between and within families. Most patients have an affected parent and the incidence of de novo variants is not known. In the cases thus far reported, all variants have resulted in amino acid substitutions.

GARS1 variants have been found in less than ten families with either CMT2D or HMNV; therefore, clinical sensitivity cannot be estimated. Analytical sensitivity should be high because all GARS1 variants reported to date or of the type expected to be detected by DNA sequencing of genomic DNA.

This test provides full coverage of all coding exons of the GARS1 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).