Whole‐exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot‐Marie‐Tooth neuropathy type 2U

Abstract

Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. We describe a 13-year-old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement. Whole-exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy. Our report highlights the importance of next-generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment.

Ubiquitously Expressed Proteins and Restricted Phenotypes: Exploring Cell-Specific Sensitivities to Impaired tRNA Charging

“…Here, we review our current understanding of ARS-related inherited diseases and propose a path forward toward defining the mechanisms that lead to tissue-specific or tissuepredominant phenotypes. in dominant Charcot-Marie-Tooth disease (CMT), an inherited neurodegenerative peripheral neuropathy that impairs motor and sensory function in the distal extremities [16][17][18][19][20]; please note that while variants in MARS1 (MIM 156560) have been reported in patients with dominant CMT [22][23][24][25][26], a genetic argument for pathogenicity has not been established [22][23][24]. Neuropathy-associated ARS variants are uniformly missense or in-frame deletion variants [17].…”

Genetic modifiers and non-Mendelian aspects of CMT

“…Three additional families have since been identified harboring likely pathogenic variants in this gene. 9,10 This has led to the concern that the field is in an asymptotic phase where, even with many new genes, the diagnostic yield may not reach 100%. This potential diagnostic gap in heritability is observed in other rare disorders as well and might be referred to as "dark matter" of clinical genomics.…”

Neurodegenerative Charcot–Marie–Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases

“…The same mutation was found in the seemingly unaffected father of a patient with the R618C allele compounded with another mutant allele in MARS, causing recessive interstitial lung and liver disease (56). The P800T mutation has been recurrently identified in multiple CMT patients (38,57,58), and the R737W mutation was reported to be a likely pathogenic variant (59). However, at this point in time, none of the cases provided unequivocal genetic evidence for the mutations to be CMT-causing.…”