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

Manu Jokela; David J. Stone; Pentti J. Tienari; Liina Kuuluvainen; Miko Valori; Hannu Laaksovirta; Minna Pöyhönen; Bryan J. Traynor; Petra Pasanen; Liisa Myllykangas; Johanna Schleutker; Anders Paetau; Saana Mönkäre; Karri Kaivola; Bjarne Udd

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

Manu Jokela
David J. Stone
Pentti J. Tienari
Liina Kuuluvainen
Miko Valori
Hannu Laaksovirta
Minna Pöyhönen
Bryan J. Traynor
Petra Pasanen
Liisa Myllykangas
Johanna Schleutker
Anders Paetau
Saana Mönkäre
Karri Kaivola
Bjarne Udd
Katso/Avaa
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LIPPINCOTT WILLIAMS & WILKINS
doi:10.1212/NXG.0000000000000335
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042824114
Tiivistelmä
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.
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