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Screening for TUBA4A mutations in a large Chinese cohort of patients with ALS: re-evaluating the pathogenesis of TUBA4A in ALS
  1. Jiao Li1,
  2. Ji He1,
  3. Lu Tang1,
  4. Lu Chen1,
  5. Yan Ma1,
  6. Dongsheng Fan1,2
  1. 1 Department of Neurology, Peking University Third Hospital, Beijing, People’s Republic of China
  2. 2 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, People’s Republic of China
  1. Correspondence to Professor Dongsheng Fan, Department of Neurology, Peking University Third Hospital, Beijing 100191, People’s Republic of China; dsfan2010{at}aliyun.com

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Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disorder with an unclear aetiology that overlaps with frontotemporal dementia (FTD). ALS is classified as either familial or sporadic, and both of these have genetic components. Knowledge of the genetic architecture of ALS has been facilitated by evolving gene-sequencing technologies. A significant excess burden of rare damaging TUBA4A variants was recently demonstrated in ALS cases via an exome scan in a case−control burden analysis.1 Several follow-up TUBA4A gene screenings were subsequently performed in ALS and FTD cohorts of Italian, Belgian and Spanish origin.2–4 However, the pathogenicity of several TUBA4A non-synonymous mutations is difficult to establish in the absence of cosegregation data, partly because ALS pedigrees are small and difficult to collect due to the late onset nature of the disorder. Here, we performed a thorough genetic analysis to determine the prevalence of TUBA4A variants in a hospital-based ALS cohort of Han Chinese origin.

Methods

In all, 113 familial ALS (fALS) index cases, 610 patients with sporadic ALS (sALS) and 1005 ethnicity-matched Chinese controls were subjected to TUBA4A sequencing using a Sanger protocol. All identified variants were further studied according to their frequency in the genome aggregation (GnomAD) database. The prediction of pathogenicity was examined using the SIFT, PolyPhen2, Mutation Tester, AASites and NetGene2 programmes.

Results

We screened the coding region of TUBA4A in 723 Chinese patients with ALS and 1005 controls, leading to the identification of three missense variants (p.I42T, …

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