1. Oligogenic basis of sporadic ALS
- Author
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Manu Jokela, Liisa Myllykangas, Bryan J. Traynor, Hannu Laaksovirta, Pentti J. Tienari, Johanna Schleutker, Liina Kuuluvainen, Miko Valori, Karri Kaivola, Bjarne Udd, David J. Stone, Anders Paetau, Petra Pasanen, Saana Mönkäre, Minna Pöyhönen, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, HUSLAB, Department of Medical and Clinical Genetics, Medicum, 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, and Minna Pöyhönen / Principal Investigator
- Subjects
0301 basic medicine ,SOD1 ,Disease ,Biology ,Compound heterozygosity ,AMYOTROPHIC-LATERAL-SCLEROSIS ,3124 Neurology and psychiatry ,CU/ZN SUPEROXIDE-DISMUTASE ,03 medical and health sciences ,0302 clinical medicine ,Genetiikka, kehitysbiologia, fysiologia - Genetics, developmental biology, physiology ,Neurologia ja psykiatria - Neurology and psychiatry ,medicine ,Amyotrophic lateral sclerosis ,Mutation frequency ,Genetics (clinical) ,Genetics ,Haplotype ,1184 Genetics, developmental biology, physiology ,3112 Neurosciences ,medicine.disease ,GENE ,Penetrance ,3. Good health ,030104 developmental biology ,ONSET ,Mutation (genetic algorithm) ,3111 Biomedicine ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
ObjectiveTo 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.MethodsAn 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.ResultsSeven 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.ConclusionsOur 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.
- Published
- 2019
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