Dissection of genetic factors associated with amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic (SALS) and only 5-10% have a family history (FALS). FALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent. While such advances have contributed to our current understanding of the causes of most cases of FALS and their underlying pathophysiological consequences, they only explain a small fraction of SALS with the etiology of most SALS cases remaining unexplained. Here, we review past and current methods used for the identification of FALS and SALS associated genes and propose a risk-based classification for these. We also discuss how the growing number of whole exome/genome sequencing datasets prepared from SALS cases, and control individuals, may reveal novel insights into the genetic etiology of SALS; for instance through revealing increased mutation burden rates across genes or genomic regions that were not previously associated with ALS or through allowing the examination of a potential "oligogenic" mechanism of the disease. Finally we summarize the three most recently discovered 'high risk' genes in ALS.
Department of Human Genetics, McGill University, Montreal, Qc, Canada; Montreal Neurological Institute and Hospital, McGill University, Montreal, Qc, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Qc, Canada.
Claire S
CS
Leblond
Montreal Neurological Institute and Hospital, McGill University, Montreal, Qc, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Qc, Canada.
Hannah M
HM
Kaneb
Montreal Neurological Institute and Hospital, McGill University, Montreal, Qc, Canada; Department of Pathology and Cellular Biology, University of Montreal, Montreal, Qc, Canada.
Patrick A
PA
Dion
Montreal Neurological Institute and Hospital, McGill University, Montreal, Qc, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Qc, Canada. Electronic address: guy.rouleau@mcgill.ca.
Guy A
GA
Rouleau
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics; D006801:Humans; D051304:Profilins / Q000235:genetics; D011506:Proteins / Q000235:genetics
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C495738:PFN1 protein, human; D051304:Profilins; D011506:Proteins
Amyotrophic lateral sclerosis; Genetic factors; Heritability; Rare disease; Whole exome sequencing