SOD1-related ALS with anticipation in a large family from Martinique

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons. ALS is mostly sporadic, but there are familial forms. In more than half of the familial forms, a pathogenic variant is found in one of the following genes: C9ORF72, SOD1, TDP-43, FUS, and VCP. SOD1 is the 2nd most common gene involved in genetic forms of ALS. Genotype–phenotype relationships are occasionally established in genetic forms of ALS associated with SOD1 mutations pathogenic variants. The c.281G > T (p.[G93V]) variant in SOD1 is associated with a rarely described and unexplained anticipation phenomenon. We report a large family from Martinique in whom ALS is associated with a c.281G > T (p.[G93V]) pathogenic variant in SOD1 and a statistically suggested anticipation. A whole-exome study and detection of CNVs (CoDESeq) from 3 affected members of this family revealed the presence of variants of uncertain signification (VUS) in other ALS genes. VUS in DCTN1 and NEFH were present in patients of the 2nd generation, and CNVs involving UBQLN2 and C21orf2 were found in the youngest case of the family.

Keywords:

• Genetic Amyotrophic Lateral Sclerosis
• anticipation
• CoDE-Seq method
• Next Generation Sequencing

Acknowledgments

The authors thank the UMR 8199 LIGAN-MP Genomics platform (Lille, France) which belongs to the “Federation de Recherche” 3508 Labex EGID (European Genomics Institute for Diabetes; ANR-10-LABX-46) and was supported by the ANR Equipex 2010 session (ANR-10-EQPX-07-01; “LIGAN-MP”). The LIGAN-PM Genomics platform (Lille, France) is also supported by the FEDER and the Region des Hauts de France. The authors also thank Dr. Martin Didier for his support in English language corrections.

Declaration of interest

The authors declare they have no conflicts of interest to disclose.