Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis

Adriano Chiò*, Cristina Moglia, Antonio Canosa, Umberto Manera, Maurizio Grassano, Rosario Vasta, Francesca Palumbo, Salvatore Gallone, Maura Brunetti, Marco Barberis, Fabiola De Marchi, Clifton Dalgard, Ruth Chia, Gabriele Mora, Barbara Iazzolino, Laura Peotta, Bryan J. Traynor, Lucia Corrado, Sandra D'alfonso, Letizia MazziniAndrea Calvo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background and ObjectivesDespite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease. MethodsThe study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A (UNC13A) (rs12608932), calmodulin binding transcription activator 1 (CAMTA1) (rs2412208), solute carrier family 11 member 2 (SLC11A2) (rs407135), and zinc finger protein 512B (ZNF512B) (rs2275294) variants, as well as ataxin-2 (ATXN2) polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 (C9orf72) GGGGCC intronic expansions (≥30). ResultsThe median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only C9orf72 (2.51 years, IQR 1.74-3.82; p = 0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p < 0.001), and UNC13AC/C(2.3 years, IQR 1.3-3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, p = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1G/G+G/Tand UNC13AC/Calleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants (p < 0.001); the survival of patients with CAMTA1G/G+G/Talleles and ATXN2≥31intermediate polyQ repeats was 1.75 years (0.84-2.18) (p < 0.001); the survival of patients with ATXN2≥31polyQ repeats and UNC13AC/Callele was 1.33 years (0.84-1.75) (p < 0.001); the survival of patients with C9ORF72≥30and UNC13AC/Callele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes. DiscussionWe showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, 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.

Original languageEnglish
Pages (from-to)E83-E93
Issue number1
StatePublished - 4 Jul 2023
Externally publishedYes


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