We searched PubMed for articles published in English between Dec 1, 2013, and Aug 31, 2017, using the search terms “ALS AND genetics” and “motor neuron disease AND genetics”. We selected articles that reported the identification of the novel amyotrophic lateral sclerosis genes MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF. We also searched for articles describing the function and implications of mutations in these selected genes in neurological and non-neurological diseases, and
Rapid ReviewNovel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications
Introduction
Typically, the disease course of amyotrophic lateral sclerosis (ALS) is rapid, and most patients die within 3–5 years of symptom onset as a result of respiratory failure.1 Although the disease is considered a rare type of motor neuron neurodegeneration, the number of patients with ALS is rapidly increasing because of population ageing. Most patients are aged between 50 and 75 years at diagnosis and, by 2040, an estimated 400 000 patients will be diagnosed with ALS worldwide.2 Approximately 10% of patients with ALS have a family history of disease, whereas the remainder of cases are classified as sporadic.1 The pathophysiology of ALS—familial or sporadic—is unclear, thus few effective treatments are available. Riluzole and edaravone are the current treatments approved for the disease. Riluzole prolongs survival by 2–3 months at best, with little effect on quality of life,3 whereas edaravone mildly improves patient mobility, but the effect on survival is unknown.4 The paucity of effective treatments warrants more genetic and molecular research on the underlying mechanisms of ALS to analyse the disease process at the cellular level. By 2014, 22 genes were implicated in ALS, and mutations in these genes account for about two-thirds of all familial cases and approximately 10% of cases of sporadic ALS.5 Since 2014, seven novel genes associated with ALS—MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF—have been identified. The rapid identification of multiple novel genes associated with ALS reflects improvements in sequencing technologies and, more importantly, provides an opportunity to better understand the disease (figure 1). Such advances are key to the development of disease-modifying treatments.
In this Rapid Review, we summarise the novel genetic discoveries associated with ALS in chronological order. We focus on the technologies and experimental design used to identify these genes, and have cross-checked genetic variants against the Exome Aggregation Consortium (ExAC) public database, which catalogues more than 7 million variants in the protein coding region of the genome identified in more than 60 000 mostly healthy individuals (ie, those without severe paediatric diseases). Genetic screening is becoming more accessible and common in clinical practice, thus understanding how a variant might cause disease within the context of the larger population could help in making reasonable inference about pathogenicity, especially when family history of disease is unknown. We also discuss the importance of these genes for the development of new therapies.
Section snippets
Novel ALS genes
Frequency data for these seven novel genes identified since 2014 are scarce because few studies have done large-scale screening of independent patient cohorts. The frequency data available for these genes are likely to be inflated, and we hypothesise that the frequency of mutations in these genes in the population will be lower when additional data is obtained. We estimated that for ALS—assuming full penetrance, no founder mutation effect, and disease prevalence of six cases per 100 000
Role of genetics in therapy development
With the exception of riluzole, which was shown to prolong survival for 2–3 months,3 and edavarone, which was shown to decrease the rate of patient immobility,4 currently no treatments are available for ALS that can effectively stop or reverse the disease progression. Diagnosis of ALS is only possible through assessment of clinical symptoms after a substantial number of motor neurons have died. Thus, for a drug to be effective, early or presymptomatic diagnosis would be necessary to prevent
Conclusions and future directions
ALS research has been largely driven by advances in our understanding of the genetics underlying the disease. This, in turn, has been fuelled by technological developments in next generation sequencing. Since 2014, seven novel genes—MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF—associated with ALS have been identified using these techniques. However, the precise disease mechanisms attributed to these genes are unclear, and further elucidation from in-vivo and in-vitro functional studies
Search strategy and selection criteria
References (70)
- et al.
The epidemiology of amyotrophic lateral sclerosis
Handb Clin Neurol
(2016) - et al.
Reassessment of Mendelian gene pathogenicity using 7855 cardiomyopathy cases and 60 706 reference samples
Genet Med
(2017) - et al.
Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis
Neurobiol Aging
(2016) - et al.
Matrin 3 variants are frequent in Italian ALS patients
Neurobiol Aging
(2017) - et al.
Mutational analysis of MATR3 in Taiwanese patients with amyotrophic lateral sclerosis
Neurobiol Aging
(2015) - et al.
MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis
Neurobiol Aging
(2016) - et al.
Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS
Biochim Biophys Acta
(2016) - et al.
Mitochondrial proteins containing coiled-coil-helix-coiled-coil-helix (CHCH) domains in health and disease
Trends Biochem Sci
(2016) - et al.
Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients
Neurobiol Aging
(2014) - et al.
CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients
Neurobiol Aging
(2015)