Open Access Case report

Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease

Hugh J McMillan1*, Jeremy Schwartzentruber2, Amanda Smith3, Suzie Lee1, Pranesh Chakraborty1, Dennis E Bulman1, Chandree L Beaulieu1, Jacek Majewski4, Kym M Boycott1 and Michael T Geraghty1

Author Affiliations

1 Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Rd, Ottawa, ON K1H 8 L1, Canada

2 McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada

3 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

4 Department of Human Genetics, McGill University, Montréal, QC, Canada

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BMC Medical Genetics 2014, 15:36  doi:10.1186/1471-2350-15-36

Published: 26 March 2014



Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy.

Case presentation

We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain.


Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.

Glycyl-tRNA synthetase; Amino acyl-tRNA synthetase; Cardiomyopathy; Charcot-Marie-tooth disease