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

• Published in: Annals of neurology 2021-04, Vol.89 (4), p.686-697
• Main Authors: Moisse, Matthieu, Zwamborn, Ramona A. J., Vugt, Joke, Spek, Rick, Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Carvalho, Mamede, Mora Pardina, Jesús S., Povedano, Monica, Andersen, Peter M., Weber, Markus, Başak, Nazli A., Chen, Xiao, Eberle, Michael A., Al‐Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Robberecht, Wim, Es, Michael, Berg, Leonard, Veldink, Jan, Van Damme, Philip
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Case-Control Studies; Cohort Studies; Copy number; Dosage; Female; Gene Dosage; Gene sequencing; Genomes; Health risks; Humans; Life Sciences; Male; Reproducibility of Results; Risk Factors; Santé publique et épidémiologie; Severity of Illness Index; SMN protein; Statistical analysis; Survival; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 2 Protein - genetics; Whole Genome Sequencing
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.26009

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