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Autosomal dominant mutations in aminoacyl\u2010tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl\u2010tRNA synthetase 1 (<jats:italic>SerRS<\/jats:italic>) for 3 families affected with CMT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD\u00a0=\u00a06.9) between the genomic co\u2010ordinates on chromosome 1: 108681600\u2013110300504. Within the linkage region, heterozygous <jats:italic>SerRS<\/jats:italic> missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2\u03b1 phosphorylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings suggest the heterozygous <jats:italic>SerRS<\/jats:italic> variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS\u2010related CMT. 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