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

Objective The role of Survival of Motor Neuron gene (SMN) 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 multicentre 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 6375 ALS patients and 2412 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; SMN2 p=0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p=0.78; SMN2 p=0.23) or age at onset (Royston-Parmar; SMN1 p=0.75; 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. This article is protected by copyright. All rights reserved.