Genetic variability in sporadic amyotrophic lateral sclerosis.

Publication

Genetic variability in sporadic amyotrophic lateral sclerosis.

Journal Paper/Review - Sep 1, 2023

Van Daele Sien Hilde, Moisse Matthieu, Farei-Campagna Jan Marino, Zwamborn Ramona A J, van der Spek Rick, van Rheenen Wouter, van Eijk Kristel R, Kenna Kevin P, Corcia Philippe, Vourc'h Patrick, Couratier Philippe, Hardiman Orla, McLaughin Russell, Gotkine Marc, Drory Vivian E, Ticozzi Nicola, Silani Vincenzo, Ratti Antonia, de Carvalho Mamede, Mora Jesus S, Povedano Monica, Andersen Peter Munch, Weber Markus, Başak Nazli A, Shaw Christopher E, Openshaw Peter J M, Morrison Karen E, Landers John E, Glass Jonathan D, van Es Michael A, van den Berg Leonard H, Al-Chalabi Ammar, Veldink Jan H, Van Damme Philip

Citation

Van Daele S, Moisse M, Farei-Campagna J, Zwamborn R, van der Spek R, van Rheenen W, van Eijk K, Kenna K, Corcia P, Vourc'h P, Couratier P, Hardiman O, McLaughin R, Gotkine M, Drory V, Ticozzi N, Silani V, Ratti A, de Carvalho M, Mora J, Povedano M, Andersen P, Weber M, Başak N, Shaw C, Openshaw P, Morrison K, Landers J, Glass J, van Es M, van den Berg L, Al-Chalabi A, Veldink J, Van Damme P. Genetic variability in sporadic amyotrophic lateral sclerosis. Brain 2023; 146:3760-3769.

Type

Journal Paper/Review (English)

Journal

Brain 2023; 146

Publication Date

Sep 1, 2023

Issn Electronic

1460-2156

Pages

3760-3769

Brief description/objective

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.