KARS1-Related Disorders via the KARS1/KARS 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 2009; Bird 2015). CMT affects approximately 1 in 3,300 people.

Recessive intermediate Charcot-Marie-Tooth type is characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. KARS1 variants have been reported in several patients with a wide variety of clinical features including intermediate CMT, developmental delay, dysmorphic features, non-syndromic hearing loss, opthalmoplegia and visual impairment, microcephaly, cognitive impairment, and seizures (Kohda et al 2016; Lieber et al 2013; McMillian et al 2015; McLaughlin et al 2010; Santos-Cortez et al 2013). Many of these cases presented in infancy, and the spectrum of clinical features is dependent upon the location of the variant in the protein (anti-codon binding domain vs. catalytic domain).

KARS1-related disorders are inherited in an autosomal recessive manner due to pathogenic variants in KARS1/KARS, located on chromosome 16q23.1. The KARS1 gene encodes the lysyl-tRNA synthetase protein which is an enzyme responsible for catalyzing the aminoacylation of tRNA^Lys with lysine. Thus far, pathogenic variants include missense and one small duplication in the KARS1 gene. In one patient, autosomal dominant inheritance was proposed; however, the reported variant's pathogenicity was not established as functional studies did not exhibit reduced enzyme kinetics (McLaughlin et al 2010). All other cases have reported autosomal recessive inheritance.

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in KARS1 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 KARS1 gene have been reported.

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