Spectrums of Amyotrophic Lateral Sclerosis. Группа авторов

FIGURE 2.1 Timeline of ALS gene discovery and the rate of genetically explained cases. (a) Cumulative number of ALS genes discovered. Each circle represents a single gene reported to cause or predispose to ALS, with the size of the circle representing the approximate proportion of cases explained. The smallest size (0%) represents genes with very rare variants or those that are not genetically implicated. (b) Total percent of ALS cases explained by variation in ALS genes over time. The cumulative percent was calculated per year corresponding to gene discovery. Estimated percent is approximate and informed by published reviews [4,54–61].

      Glycosyltransferase 8 Domain Containing 1 (GLT8D1)

      In an experimental paradigm similar to ANXA11, variants in GLT8D1 were observed in familial ALS cases [67]. Exome sequencing was used to identify rare and predicted deleterious variants that segregated well with the disease phenotype, resulting in candidate genes GLT8D1 and ARPP21. Several patients carried both the ARPP21 p.P529L and GLT8D1 p.R92C variants, each of which could have been the causal factor. However, an examination of variants identified by the large‐scale ALS Project MinE [68] revealed a larger number of ALS cases carrying the GLT8D1 variant without any ARPP21 variants than the same variant with the ARPP21 variant. The gene GLT8D1 encodes a glycosyltransferase protein, which the authors note is not typically implicated in ALS and might represent a new avenue to investigate for ALS neurodegeneration [67].

      Stathmin‐2 (STMN2)

      The loss‐of function hypothesis for TDP‐43 has led to the examination of transcripts that are dysregulated following TARDBP knockdown. In separate studies, TARDBP was silenced in human motor neurons derived from iPSC as well as in TARDBP variant carrier cell lines [69, 70]. The primary objective of both studies was to identify transcripts that showed significant expression differences after TARDBP depletion; while the overlap of transcripts between the studies has not been examined, both studies identified Stathmin‐2 (STMN2). The studies further show that certain TARDBP variants also cause a similar downregulation of STMN2 compared to unaffected controls. Moreover, an aberrant exon and subsequent truncation were observed in STMN2 transcripts following TARDBP silencing, further supporting the cryptic exon mechanism of TDP‐43 dysregulation in ALS.

      As a component of microtubule dynamics, STMN2 adds to a group of genes implicated in the regulation of assembly and disassembly of tubulin (TUBA4A [71]) and movement of molecular cargo along microtubule networks (KIF5A [72, 73] and DCTN1 [71]). While no publications have shown variants in STMN2 associated with ALS, STMN2 dysregulation expands our knowledge about TDP‐43 binding pre‐mRNA transcripts in the nucleus. Both studies identified STMN2 as a TDP‐43 target using motor neuron cultures, demonstrating the necessity of specific cellular models.

ASPECTS OF ALS HERITABILITY

      Despite the number of genes associated with ALS, a very low percentage of patients carry a variant in one of these genes. As many as 30% of familial and 90% of sporadic ALS cases can be deemed as “no known genetic cause” [4] – either their disease was caused primarily by environmental factors, or they carry a not‐yet‐identified causal variant (or variants).

      Sporadic vs. Familial

      Historically, a patient without a family history of ALS was designated as sporadic, while those with at least one relative with ALS were familial cases. Despite different genetic backgrounds, sporadic and familial ALS patients have the same spectrum of signs and symptoms. For a disease that has a very low prevalence and a short duration (onset to death), accurate family history likely is not recorded for many sporadic ALS patients [74–76]. Further, while the population risk of ALS in relatives of sporadic ALS patients is up to eight times greater than the general population, an individual has a far greater chance of having a fatal heart condition or cancer [77] and would therefore never be considered in an ALS pedigree.

      It might be possible to re‐classify ALS into either known‐genetic or unknown‐genetic causes. Causal variants are found in similar genes in both familial and sporadic ALS [4]. This overlap is more pertinent to the penetrance or average age at onset of specific variants than it is for whether a variant leads to sporadic or familial ALS. However, the distinction between familial and sporadic has been historically helpful in finding new genes. Families with autosomal‐dominant ALS and sufficiently early age at onset to avoid unaffected carriers have allowed the discovery of the most penetrant and severe variants. Conversely, the sporadic model of ALS has allowed the discovery of de novo variants, those that arise from the germline cells of the parents [78]. While a very rare cause of sporadic ALS, validated and repeatedly observed de novo variants in FUS (primarily the p.P525L variant) [79, 80] have been reported. Whether familial/sporadic or known/unknown cause is the better choice to describe ALS inheritance will require more genetic research.

      Penetrance and the Oligogenic Hypothesis

      A small percentage of ALS cases carry more than one variant of an ALS gene [81–83]. Moreover, while the penetrance of SOD1, TARDBP, FUS, and C9orf72 variant carriers can reach upward of 95% [84], there are always rare asymptomatic carriers [85]. Often, variants that arise in ALS genes of uncertain penetrance are extremely rare, and it is difficult to calculate the penetrance of a variant that has been observed in a single patient or family [4]. Such observations led to the oligogenic hypothesis in ALS: multiple variants in multiple ALS genes are necessary for ALS.

The oligogenic hypothesis is useful to frame the genetic discussion about ALS, but it should be used in specific circumstances. In patients carrying several variants in ALS genes, the age of symptom onset tends to be significantly earlier [81]. The rapidity and severity of symptoms are also increased with each additional variant observed in ALS genes. However, considering that cases with multiple ALS variants constitute a low percentage (approximately 1%) of all ALS patients [86], and because variants in ALS genes tend to have high predicted severity and effects on cellular function, it is likely that a single variant is sufficient to instigate the disease in most cases. Further, as most oligogenic cases are those with C9orf72 HRE [86, 87], and the HRE is highly penetrant at later ages [84], oligogenic ALS cases likely explain disease severity rather than necessity. To better explore the oligogenic hypothesis, variant penetrance and severity should be considered before labeling a multi‐variant case as oligogenic.

      Multistep Model

      In comparison with the oligogenic model, a multistep model posits that ALS can be considered in terms of discrete etiological steps that each sequentially contributes to disease [8, 88]. Similar to cancer models, a single germline variant may be tolerated and not directly result in disease, but coupled with environmental exposure, additional variants, age‐related cellular damage, or yet unknown factors, ALS may rapidly occur once a step threshold has been reached [8, 88]. Because ALS has a strong association with increasing age [89], the multistep model is a logical framework to account for cell stress due to either long‐term environmental