A Systematic Review of Genotype-Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS.

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease's genotype-phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.

Homozygosity mapping in an Irish ALS case-control cohort describes local demographic phenomena and points towards potential recessive risk loci.

Runs of homozygosity are common in European populations and are indicative of consanguinity, restricted population size and recessively inherited traits. Here, we map runs of homozygosity (ROHs) in an Irish case-control cohort for amyotrophic lateral sclerosis (ALS), a devastating neurological condition with high heritability yet only partially established genetic cause. We compare the extent of homozygosity in the Irish cohort with a large British cohort and observe that ROHs are longer and more frequent in the Irish population than in the British, and that extent of ROHs is correlated with demographic factors within the island of Ireland. ROHs are also longer and more frequent in ALS cases compared to population-matched controls, supporting the hypothesis that recessively inherited loci play a pathogenic role in ALS. Comparing homozygous haplotypes between cases and controls reveals several potential recessive risk loci for ALS, including a genomic interval spanning ARHGEF1, a compelling ALS candidate gene.

Second-generation Irish genome-wide association study for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a heritable neurological disease for which the underlying genetic etiology is only partially understood. In Ireland, 83%-90% of cases are currently unexplained. Through large international collaborations, genome-wide association studies (GWASs) have succeeded in identifying a number of genomic loci that contribute toward ALS risk and age at onset. However, for the large proportion of risk that remains unexplained, population specificity of pathogenic variants could interfere with the detection of disease-associated loci. Single-population studies are therefore an important complement to larger international collaborations. In this study, we conduct a GWAS for ALS risk and age at onset in a large Irish ALS case-control cohort, using genome-wide imputation to increase marker density. Despite being adequately powered to detect associations of modest effect size, the study did not identify any locus associated with ALS risk or age at onset above the genome-wide significance threshold. Several speculative associations were, however, identified at loci that have been previously implicated in ALS. The lack of any clear association supports the conclusion that ALS is likely to be caused by multiple rare genetic risk factors. The findings of the present study highlight the importance of ongoing genetic research into the cause of ALS and its likely future challenges.

Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.

BACKGROUND: Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts. METHODS: Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls. RESULTS: Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10(-4)). CONCLUSIONS: Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.