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

Matthieu Moisse ,Russell L Mclaughlin ,Ammar Al‐Chalabi ,Vincenzo Silani ,Jesús Mora ,Brendan Kenna ,Marc Guillaume ,Vivian E Drory ,Kevin P Kenna ,Michael A Eberle ,Patrick Vourc’h ,Rick A A Van Der Spek ,Philippe Corcia ,Philippe Couratier ,Michael A Van Es ,Joke J.f.a Van Vugt ,Michael Benatar ,Kristel Van Eijk ,Christopher E Shaw ,Jonathan D Glass ,Orla Hardiman ,Wim Robberecht ,Mamede De Carvalho ,Pamela J Shaw ,Nicola Ticozzi ,Wouter Van Rheenen ,Karen Morrison ,Jan H Veldink ,Mónica Povedano ,Markus Weber ,Leonard H Van Den Berg ,John E Landers ,A Nazlı Başak ,Xiao Chen ,Ramona A J Zwamborn ,Philip Van Damme

doi:10.1002/ana.26009

Abstract

ObjectiveThe 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.MethodsIn 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.ResultsThe 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).InterpretationIn 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

Highlights

This set was further compared with the results of SMNCNC, with a concordance of 99.3% and 99.5% for SMN1 and SMN2, respectively, which is similar to previous findings (Figs 1 and 2).[24]
survival of motor neuron (SMN) copy number (CN) as a Modifier for amyotrophic lateral sclerosis (ALS) As the CN of SMN has been proposed as a disease modifier, we investigated the effect on age at onset and survival.[10,15]
In a large cohort of patients with ALS for which SMN1 and SMN2 CNs have been assessed, shows that no association can be found between the CN of the SMN genes and ALS risk or disease severity

Summary

Objective

The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. Previous studies investigating the effect of the CNs of SMN on disease risk and progression of ALS have reported conflicting results.[6,7,8,9,10,11,12,13,14,15] According to some studies, loss of SMN1 is associated with ALS risk,[8,9,12] whereas others found that duplication of SMN1 associated with ALS risks.[6,7,11,12,13] Others did not find any association between ALS and the number of SMN1 copies.[10,14,15] Likewise for SMN2, some found a homozygous deletion to be protective,[8] whereas others found the deletion to be more frequent in ALS and reducing the survival time of these patients.[9,10,15] In addition, here, several other publications failed to find any association.[6,7,11,12,13,14] In this large study, we aimed to use the whole genome sequencing (WGS) data from Project MinE, which contains 6,375 patients with ALS and 2,412 controls to evaluate the effect of SMN CNs in the context of ALS risk and clinical phenotype.[21] This is the largest ALS cohort in which SMN genes have been analyzed in the hope to find a definitive answer

Methods

Results

Discussion