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. 2025 Aug;32(8):e70302.
doi: 10.1111/ene.70302.

Prevalence of SOD1 and C9orf72 Variants Among French ALS Population: The GENIALS Study

P Corcia  1   2   3   4 , D Erazo  5   6 , M D M Amador  7   8 , S Beltran  1   2   3 , E Bernard  9 , H Blasco  2   10 , C Boutoleau-Bretonniere  11 , G Bruneteau  4   7   8 , J P Camdessanche  12 , W Camu  13 , J Cassereau  14   15 , A Choumert  16 , P Codron  14   15 , P Cintas  17 , E De La Cruz  13 , V Danel  18 , C Desnuelle  19   20 , N Eyraud  1   2   3 , F Esselin  13 , A L Fauret  21 , M Lefilliatre  22 , M C Fleury  23 , S Genestet  24 , A M Grapperon  3   25 , N Guy  26 , A Jacquin-Piques  27 , K Beauvais  27 , G Lautrette  3   5   6 , G Le Masson  28 , S Mathis  28 , A S Piegay  1   2   3 , S Pittion-Vouyovitch  29 , P Sauleau  30 , M H Soriani  19   20 , A Vershueren  3   25 , K Mouzat  31 , C Guissart  31 , P Couratier  4   5   6 , P Vourc'h  2   10
Affiliations

Prevalence of SOD1 and C9orf72 Variants Among French ALS Population: The GENIALS Study

P Corcia et al. Eur J Neurol. 2025 Aug.

Abstract

Rationale: Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease in which genetics plays a central role for both familial and sporadic ALS cases. Systematic genetic analysis for all ALS patients is recommended at the time of diagnosis, leading to an early proposal of specific genetic therapy. Currently, C9orf72 is considered the most frequently mutated gene in ALS. Patients with a SOD1 pathogenic or probably pathogenic variants (ACMG classification) are eligible for SOD1 antisense oligonucleotide therapy.

Objective: To determine the frequency of SOD1 variants and C9orf72 G4C2 repeats in a French ALS population and to describe genotype-phenotype relationships.

Material and methods: One thousand incident ALS patients were enrolled from 22 ALS centers in France and followed up for 12 months. Epidemiological, familial history, neurological data, and genetic status were collected.

Main results: C9orf72 G4C2 repeats and SOD1 variants were observed in 7.6% and 1.6%, respectively. Fifty percent of SOD1 patients and 51% of C9orf72 patients had sporadic ALS. Fifteen different SOD1 variants were identified within the five exons and one intron. C9orf72 patients had a significantly younger age at onset and a trend toward a faster progression compared to non-expanded C9orf72 patients. Moreover, among the non-SOD1 non-C9orf72 population, patients with at least one C9orf72 copy with two G4C2 repeats had a shorter disease duration.

Conclusion: This study confirms SOD1 variants low frequency in the French population and highlights the more rapid disease progression observed in patients carrying C9orf72 expansions. These findings underscore the importance of systematic genetic screening at diagnosis.

Keywords: ALS‐C9orf72‐SOD1; ALS‐familial; correlation; genotype–phenotype; sporadic.

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Conflict of interest statement

The authors declare no conflicts of interest. P. Corcia, P. Couratier, E. Bernard, and JP Camdessanche received personal fees from Biogen for consulting, but this was not related to this study.

Figures

FIGURE 1
FIGURE 1
Schematic representation of SOD1 gene and the fifteen mutations identified in the GENIALS population. The SOD1 gene is located in the region 21q22.11 of chromosome 21 and is composed of five exons (in yellow) and four introns (in blue). Fourteen variants were identified in the five exons and one in intron 4.
FIGURE 2
FIGURE 2
Progression of the disease by genetic status; the GENIALS study. (A) Anova repeated measures for ALSFRS‐R score (SOD1 n = 11, C9orf72 n = 45, non‐SOD1 non‐C9orf72 n = 464) Friedman test p < 0.001. (B) Anova repeated measures for ALSFRS‐R slope decline (SOD1 n = 11, C9orf72 n = 45, non‐SOD1 non‐C9orf72 n = 457) Friedman test p = 0.02.
FIGURE 3
FIGURE 3
Weight loss distribution, the GENIALS study. T0: Between onset and diagnosis (SOD1 = 16; C9orf72 n = 73, non‐SOD1 non‐C9orf72 n = 876) p = 0.201; T6: Between first visit and second visit at 6 months of inclusion (SOD1 = 12; C9orf72 n = 58, non‐SOD1 non‐C9orf72 n = 666) p = 0.618; T12: Second visit and last visit at 12 months of inclusion (SOD1 = 10; C9orf72 n = 48, non‐SOD1 non‐C9orf72 n = 465) p = 0.047. Y axis (%). X axis weight loss group (no weight loss, less than 5%, between 5% and 10% of weight loss, and more than 10% of weight loss).
See this image and copyright information in PMC

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