Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders.

Wai Yan Yau,Roisin Sullivan,Henry Houlden,Hiroyuki Ishiura,Anna Zecchinelli,Malgorzata Murray,Zhongbo Chen,Chris Turner,Viorica Chelban,Stefano Duga,Jana Vandrovcova,Nicholas W Wood,Susana Carmona,Roberto Cilia,Genomics England Research Consortium ,Zane Jaunmuktane,Shoji Tsuji

doi:10.1002/mds.28302

Abstract

BackgroundThe objective of this study was to determine the prevalence of the GGC‐repeat expansion in NOTCH2NLC in whites presenting with movement disorders.MethodsWe searched for the GGC‐repeat expansion in NOTCH2NLC using repeat‐primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with “possible” or “probable” MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat‐primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long‐read sequencing.ResultsWe identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project.ConclusionsGGC‐repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole‐genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Highlights

205 (1.5%), and 5 of 189 (2.6%) Chinese families with essential tremor (ET), Parkinson’s disease (PD), and multiple system atrophy (MSA), respectively.[5,6,7] These findings suggest that this repeat expansion may be involved in the pathogenesis of ET, PD, and MSA in the East Asian population
We manually visualized the ExpansionHunter analysis of whole-genome swequencing (WGS) data in patients with ≥58 repeats for which DNA was available for repeat-primed polymerase chain reaction (RP-PCR): only 1 patient carried the expansion
We report 2 patients carrying the GGC-repeat expansion in NOTCH2NLC: 1 patient presenting with autosomal-dominant ET and the other patient presenting with recurrent encephalopathy and postural tremor/ parkinsonism mimicking mitochondrial disorders

Summary

Introduction

205 (1.5%), and 5 of 189 (2.6%) Chinese families with essential tremor (ET), Parkinson’s disease (PD), and multiple system atrophy (MSA), respectively.[5,6,7] These findings suggest that this repeat expansion may be involved in the pathogenesis of ET, PD, and MSA in the East Asian population. We aimed to establish the prevalence of GGC-repeat expansion in NOTCH2NLC in white patients with movement disorders

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Conclusion