Fifty-four percent of patients with ALS carried at least one detrimental common variant or repeat expansion, highlighting the clinical impact of gene variants as modifiers in ALS.
In a recently published study in Neurology, findings showed that gene variants and expansions can have differential effects on survival in patients with ALS when acting on their own or in unison. The results provide insight into the genetic modifiers of survival and phenotype in ALS, highlighting the importance of these factors in clinical trials to understand the disease's heterogeneity.1
Among the cohort of 1,245 patients with ALS, the median survival time was 2.67 years (IQR, 1.67-5.25). The genetic variants of C9orf72 (range, 2.51 years; IQR 1.74-3.82; P = .016), ATXN2 (range, 1.82 years; IQR, 1.08-2.33; P <.001) and UNC13AC/C (range, 2.3 years; IQR, 1.3-3.9; P <.001) were the only ones that significantly reduced survival. Notably, the variant CAMTA1 was found to be independently related to survival independently (HR, 1.13; 95% CI, 1.001-1.30; P = .048).
Lead author Adriano Chiò, MD, professor of neurology at the University of Turin in Italy, and colleagues wrote, “Our study highlights the importance of genetic factors in the progression of ALS and suggests that the cooccurrence of multiple pathogenic variants related to ALS is associated with a worse prognosis for patients."1 The study investigated if the copresence of genetic variants related to ALS had any interactive effects on the progression of the disease and clinical outcomes in patients.
The study consisted of patients diagnosed with ALS who did not carry the pathogenic variants of SOD1, TARDBP and FUS, between 2007 and 2016 from the Piemonte Register.2,3 The 766 controls included were case match-selected by sex, age, and geographical location. Whole genome sequencing was performed on both the subset of participants with ALS and the controls. The specific genes explored in the study included UNC13A, CAMTA1, SLC11A2, and ZNF512B, as well as C9orf72 repeat expansions and ATXN2 polyQ intermediate repeats. Investigators assessed the effect of individual genes on survival by conducting a multivariable analysis, and evaluating gene pair interactions.
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"The identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results," Chiò et al noted.1 The copresence of 2 detrimental alleles or expansions was associated to shorter survival in patients with ALS. Authors observed that specific survival outcomes were linked to different combinations of the genetic variants.
Patients with the variant CAMTA1G/G+G/T and UNC13AC/C alleles had a median survival of 1.67 years (1.16-3.08), compared with 2.75 years (1.67-5.26) for those without these variants (P <.001). Similarly, patients with the variant CAMTA1G/G+G/T alleles and ATXN2≥31 intermediate polyQ repeats had a median survival of 1.75 years (0.84-2.18; P <.001). Additionally, the coexistence of ATXN2≥31 polyQ repeats and UNC13AC/C allele correlated to a median survival of 1.33 years (0.84-1.75;(P <.001), while patients with C9orfF72≥30 and UNC13AC/C allele had a median survival of 1.66 years (1.41-2.16).
The study's strength is the population-based design which captured a significant portion of incident cohort patients from specific regions, in comparison with the design of prevalent-based studies. Despite the study’s strength, it did not assess the impact of genetic interactions on cognition because of incomplete testing for cognitive function in some of the patients. Another limitation was the number of patients who carried certain combinations of genetic variants, restricting the analysis of that certain phenotype. Thus, authors noted larger patient cohorts could further explore these combinations and external replication of the results in other populations would confirm its observations.
Chiò et al wrote, "This study emphasizes the need for further research into the genetic factors that contribute to ALS, which may ultimately lead to improved diagnosis and treatment options for patients."1