Affiliations: [a] Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
| [b] Division of Neurology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
| [c] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
| [d] Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| [e] Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
Correspondence to: Kym M. Boycott, MD, PhD, Department of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, K1H 8L1, ON, Canada. Tel.: +1 613 737 7600 /Ext 4139; Fax: +1 613 738 4822; E-mail: firstname.lastname@example.org.
Abstract: Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, an axonal sensorimotor polyneuropathy with adult-onset, slowly progressive disease reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity.