Oligogenic basis of sporadic ALS The example of SOD1 p.Ala90Val mutation

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Kuuluvainen , L , Kaivola , K , Mönkäre , S , Laaksovirta , H , Jokela , M , Udd , B , Valori , M , Pasanen , P , Paetau , A , Traynor , B J , Stone , D J , Schleutker , J , Pöyhönen , M , Tienari , P J & Myllykangas , L 2019 , ' Oligogenic basis of sporadic ALS The example of SOD1 p.Ala90Val mutation ' , Neurology Genetics , vol. 5 , no. 3 , 335 . https://doi.org/10.1212/NXG.0000000000000335

Title: Oligogenic basis of sporadic ALS The example of SOD1 p.Ala90Val mutation
Author: Kuuluvainen, Liina; Kaivola, Karri; Mönkäre, Saana; Laaksovirta, Hannu; Jokela, Manu; Udd, Bjarne; Valori, Miko; Pasanen, Petra; Paetau, Anders; Traynor, Bryan J.; Stone, David J.; Schleutker, Johanna; Pöyhönen, Minna; Tienari, Pentti J.; Myllykangas, Liisa
Contributor organization: HUSLAB
Department of Medical and Clinical Genetics
University of Helsinki
Research Programme for Molecular Neurology
Research Programs Unit
HUS Neurocenter
Department of Neurosciences
Pentti Tienari / Principal Investigator
Neurologian yksikkö
University Management
Department of Pathology
Minna Pöyhönen / Principal Investigator
Date: 2019-06
Language: eng
Number of pages: 6
Belongs to series: Neurology Genetics
ISSN: 2376-7839
DOI: https://doi.org/10.1212/NXG.0000000000000335
URI: http://hdl.handle.net/10138/306380
Abstract: Objective To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 (SOD1) p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance. Methods An index patient with autopsy-proven ALS was discovered to have the SOD1 p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data. Results Seven screened patients (1.5%) were found to carry the SOD1 heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare ANG and SPG11 mutations. One patient was compound heterozygous for SOD1 p.Ala90Val and p.Asp91Ala. Conclusions Our data suggest that the penetrance of SOD1 p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the SOD1 founder mutation.
3111 Biomedicine
1184 Genetics, developmental biology, physiology
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion

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