Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications

Abstract

Background: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS.

Recent developments: Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.

Figure 1. Genetic landscape of ALS between 1993 and 2016

Familial ALS cases constitute about 10% of all cases of ALS. Of this 10%, about 70% can be explained by genetics. Two substantial increases in genetic contribution to ALS were found in 2008 and 2011, corresponding to the identification of TARDBP (contributes to about 4% of familial and 1% of sporadic cases) and C9orf72 (contributing to about 40% of familial cases and 8% of sporadic cases). ALS=amyotrophic lateral sclerosis. GWAS=genome-wide association study. WGS=whole-genome sequencing. WES=whole-exome sequencing. NGS=next-generation sequencing. RP-PCR=repeat-primed polymerase chain reaction. SNP=single nucleotide polymorphism. ASO=antisense oligonucleotide.

Figure 2. Interactions between genes associated with amyotrophic lateral sclerosis

The outer circle is a karyotype ideogram showing 24 chromosomes (22 autosomal chromosomes, X chromosome, and Y chromosome); the inner circle shows the location of each gene. Links between genes represent interactions at the protein or gene level. Interaction data was obtained from the Biological General Repository for Interaction Datasets. Black lines indicate cytogenetic band patterns. Biological processes implicated in either the gene or interactions are indicated by colour.