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
StatePublished - Apr 2021
Externally publishedYes


FundersFunder number
E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
Italian Ministry of HealthRF‐201302355764
MND Association
Maudsley Biomedical Research Centre
National Institute of Neurological Disorders and StrokeR01NS073873
Wellcome Trust
Horizon 2020 Framework Programme772376 ‐ EScORIAL
EU Joint Programme – Neurodegenerative Disease Research
Medical Research CouncilBRAIN‐MEND, MR/R024804/1, MR/L501529/1, 733051071
National Institute for Health Research
Motor Neurone Disease Association
European Research Council
Science Foundation Ireland17/CDA/4737
Agentschap voor Innovatie door Wetenschap en Technologie
KU Leuven
Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica
Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
Fondazione per la Ricerca Biomedica2015–0023


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