RT Journal Article
SR Electronic
T1 Oligogenic basis of sporadic ALS
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e335
DO 10.1212/NXG.0000000000000335
VO 5
IS 3
A1 Kuuluvainen, Liina
A1 Kaivola, Karri
A1 Mönkäre, Saana
A1 Laaksovirta, Hannu
A1 Jokela, Manu
A1 Udd, Bjarne
A1 Valori, Miko
A1 Pasanen, Petra
A1 Paetau, Anders
A1 Traynor, Bryan J.
A1 Stone, David J.
A1 Schleutker, Johanna
A1 Pöyhönen, Minna
A1 Tienari, Pentti J.
A1 Myllykangas, Liisa
YR 2019
UL http://ng.neurology.org/content/5/3/e335.abstract
AB 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.ALS=amyotrophic lateral sclerosis; IHC=immunohistochemistry; SOD1=superoxide dismutase 1; WES=whole-exome sequencing; WGS=whole-genome sequencing