Improving ALS Molecular Diagnosis Through Functional Assays: Reassessment of a SOD1 Variant of Uncertain Significance
Genetic testing in amyotrophic lateral sclerosis (ALS) often reveals variants of uncertain significance (VUS), which are frequently omitted from diagnostic reports or reported with limited clinical interpretation. To address this gap, we developed a rapid functional assessment pipeline in collaboration with FILSLAN, the French ALS care network, combining in vitro and in vivo neurogenetic assays. We illustrate this approach through the reclassification of the <i>SOD1</i> p.Val120Leu variant, identified in an ALS patient, as pathogenic. Functional studies demonstrated that this variant leads to cytoplasmic aggregation, reduced neurite outgrowth, and abnormal motor behavior in zebrafish. These results support the systematic use of functional assays to clarify the pathogenicity of uncertain variants, thereby improving diagnostic accuracy, preventing misdiagnosis, and enabling timely therapeutic interventions in ALS.
Authors
- Annie Verschueren (ORCID: https://orcid.org/0000-0003-1266-9062)
- Cédric Raoul (ORCID: https://orcid.org/0000-0003-0561-6851)
- Philippe Couratier
- Charlotte Veyrat‐Durebex (ORCID: https://orcid.org/0000-0003-4512-2303)
- Claire Guissart (ORCID: https://orcid.org/0000-0002-3944-5715)
- Sylviane Marouillat (ORCID: https://orcid.org/0000-0001-7918-9755)
- Aleksandra Chudinova
- Chloé Boisseau (ORCID: https://orcid.org/0000-0002-8106-7009)
- Serge Lumbroso (ORCID: https://orcid.org/0000-0002-7373-5046)
- Hélène Blasco (ORCID: https://orcid.org/0000-0001-6107-0035)
- Christian Andrés (ORCID: https://orcid.org/0000-0002-5062-3156)
- Kévin Mouzat (ORCID: https://orcid.org/0000-0003-3832-9883)
- Patrick Vourc’h (ORCID: https://orcid.org/0000-0001-7960-8139)
- Philippe Corcia
- Léa Bedja-Iacona
- Arthur Forget
Institutions
- Université de Tours (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Laboratoire de Biologie et Modélisation de la Cellule (FR)
- Laboratoire National de Référence (MA)
- Centre Hospitalier Universitaire de Limoges (FR)
- Institute for Neurosciences of Montpellier (FR)
- Université de Nîmes (FR)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-08-01
- DOI
- https://doi.org/10.3390/ijms26157414
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone
- Centre Hospitalier Universitaire de Nîmes