Affiliations: [a] Bristol Genetics Laboratory, North Bristol Trust, Bristol, UK
| [b] John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| [c] Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| [d] Istituto Neurologico Carlo Besta, Milan, Italy
| [e] Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK | [f] Gloucester Royal Infirmary, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK
| [g] Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
Norfolk and Norwich University Hospital, Norwich, UK
University Hospitals Bristol NHS Foundation Trust, Bristol, UK
Correspondence to: Dr Anirban Majumdar, Department of Paediatric Neurology, 6th Floor Education Centre, Upper Maudlin St, Bristol, BS2 8BJ, UK. Tel.: +44 0117 342 0502; E-mail: [email protected].
Abstract: Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies.
Keywords: Aminoacyl-tRNA synthetases, Charcot-Marie-Tooth disease, distal hereditary motor neuropathy, Glycyl-tRNA synthetase, Next Generation Sequencing, peripheral neuropathies