The Effect of SMN Gene Dosage on ALS Risk and Disease Severity

Matthieu Moisse, Ramona A J Zwamborn, Joke van Vugt, Rick van der Spek, Wouter van Rheenen, Brendan Kenna, Kristel Van Eijk, Kevin Kenna, Philippe Corcia, Philippe Couratier, Patrick Vourc'h, Orla Hardiman, Russell McLaughin, Marc Gotkine, Vivian Drory, Nicola Ticozzi, Vincenzo Silani, Mamede de Carvalho, Jesús S Mora Pardina, Monica PovedanoPeter M Andersen, Markus Weber, Nazli A Başak, Xiao Chen, Michael A Eberle, Ammar Al-Chalabi, Chris Shaw, Pamela J Shaw, Karen E Morrison, John E Landers, Jonathan D Glass, Wim Robberecht, Michael van Es, Leonard van den Berg, Jan Veldink, Philip Van Damme

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OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.

Original languageEnglish
Pages (from-to)686-697
Number of pages12
JournalAnnals of neurology
Issue number4
Early online date15 Jan 2021
Publication statusPublished - Apr 2021

Bibliographical note

© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.


  • Amyotrophic Lateral Sclerosis/genetics
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Gene Dosage
  • Humans
  • Male
  • Reproducibility of Results
  • Risk Factors
  • Severity of Illness Index
  • Survival of Motor Neuron 1 Protein/genetics
  • Survival of Motor Neuron 2 Protein/genetics
  • Whole Genome Sequencing


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