Discussion

Individuals predisposed to late-onset neurodegenerative diseases such as ALS are subject to age-related cumulative risks of developing these disorders. Genetically determined forms of ALS will therefore always exhibit some degree of incomplete penetrance owing to confounding variables that may affect the lifespan of at-risk individuals. This can often be seen when assessing an affected individual’s family history, for example, where an intervening relative who is an obligate gene carrier has died at a relatively young age and thus would appear to have been unaffected, potentially leading to underestimation of penetrance. To complicate matters further, there is currently no reliable way to ascertain whether or not a deceased at-risk individual (eg, a carrier of an apparently pathogenic SOD1 variant) would have gone on to develop neurodegeneration. This makes measuring the true penetrance of genes predisposing to ALS problematic.

This study has sought to estimate ALS gene penetrance by reference to published and publicly available information. The calculated penetrance estimates depend heavily on the accuracy of the epidemiological figures employed. A number of additional inherent limitations also apply. First, there are undoubtedly multiple and substantial non-genetic and environmental influences on ALS and we have not sought to address these factors in this purely genetic analysis. Second, this study assumes that the population in gnomAD is an accurate surrogate for the general population. Third, no allowance has been made for different rates of ALS gene variants across different ethnic groups, for which good evidence exists.7 Fourthly, the analysis assumes that ClinVar annotations are accurate and does not take into account the substantial numbers of variants present in gnomAD that are not present in ClinVar and which therefore have not been classified. Finally, by performing analysis at the gene level, no consideration has been given to the possible variability in penetrance that might be attributable to specific gene variants.

In defence of the relatively simplistic approach used here, it should be noted that gnomAD v.2.1.1 does indeed have a large preponderance of data from European ancestry individuals.18 The ALS gene contribution figures used have also been largely ascertained in respect to European ancestry cohorts and so these are likely to be applicable.6 We have sought to use generally accepted figures for percentage gene contributions to ALS and FTD but recognise that uncertainty exists, particularly for figures under 1% and so we have not included values below 1% and similarly have limited the analysis to only the four most commonly involved ALS genes. In addition, we have sought to maximise the expected number of variants (and hence to maximise the calculated gene penetrance) by using a fALS rate of 10% rather than 5% and by including lifetime risks of ALS (1 in 386) and FTD (1 in 305) that are towards the upper limits for what has been reported or calculated according to incidence. Furthermore, by only counting variants classified unambiguously on ClinVar, we believe that we have in fact underestimated the true frequencies of observed pathogenic and likely pathogenic variants, which if included would further increase the observed/expected variant ratios and therefore decrease the penetrance of each gene even further. By limiting our analysis to ALS and FTD, we have precluded the possibility of other forms of neurodegeneration being caused by these gene variants. However, widely accepted figures for such contributions are generally not available and we have therefore chosen to omit these. With regard to variant-level effects, such differences are indeed likely to exist and further research into the reasons for genotype-specific disease variability may prove fruitful in terms of understanding the pathogenic mechanisms underlying genetic forms of ALS and FTD. However, the results of this study would tend to caution against the automatic attribution of penetrance figures to individual variants, since the implication of this work is that penetrance is not an intrinsic characteristic of a given gene or variant but rather is modifiable and dependent on other genetic and non-genetic factors. In any case, the numbers of variants in the gnomAD cohort are too low to allow adequate analysis to this level of detail and this will only start to become possible with reference to genomic data cohorts that include millions of individuals.

In this study, we have identified that pathogenic and likely pathogenic variants in commonly identified genes linked to ALS are over-represented in control populations and therefore display reduced penetrance at the population level. This finding is of relevance to understanding the aetiology and pathogenesis of ALS and FTD and raises the question of what factors, genetic or otherwise, are influencing the penetrance in this way. It also has important clinical implications for those undertaking genetic testing of individuals affected by ALS and FTD and even more so for the predictive genetic testing of unaffected relatives. Now that clinical trials are taking place to target SOD1 and C9orf72 gene carriers, it is becoming critical to understand who will and who will not go on to develop disease and hence who is likely to benefit most and least from such treatments.20 Importantly, it should be noted that the penetrance figures reported here apply only to the population as a whole, not to the individual. It would therefore not be appropriate to counsel affected individuals and their relatives based solely on these figures. Individual carriers of disease-causing variants in these genes are likely to have individualised risk profiles and this should be considered carefully when making clinical decisions about predictive testing. Until such time as the other relevant factors influencing ALS gene penetrance become known and their relative contributions understood, an individual’s risk will likely best be determined by reference to his or her own family history of the disease.