Genetic variability in sporadic amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Genetics
• Genomics

Background:

• Gene therapies for amyotrophic lateral sclerosis (ALS) are emerging, increasing the demand for genetic testing.
• Genetic variation in sporadic ALS (sALS) is complex, with scarce large-scale studies on all associated genes.
• Current gene testing guidelines and patient counseling for sALS are lacking.

Purpose of the Study:

• To characterize genetic variability in ALS-associated genes using whole genome sequencing data from a large sALS cohort.
• To apply American College of Medical Genetics and Genomics (ACMG) criteria for identifying pathogenic and likely pathogenic variants.
• To investigate repeat expansions in key ALS genes and analyze combinations of variants.

Main Methods:

• Whole genome sequencing of 6013 sALS patients and 2411 controls from Project MinE.
• Application of customized ACMG criteria to 90 ALS-associated genes.
• Utilized ExpansionHunter for repeat expansion length determination in C9orf72, ATXN1, ATXN2, and NIPA1.

Main Results:

• Pathogenic or likely pathogenic variants identified in 11.13% of sALS patients across 38 genes, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN, or TBK1.
• C9orf72 repeat expansions found in 5.21% of sALS patients.
• Significantly more sALS cases carried pathogenic/likely pathogenic variants (OR 1.75) and combinations of variants compared to controls.

Conclusions:

• This study provides a comprehensive inventory of pathogenic genetic variation in a large sALS cohort.
• Identified genetic variants in 11.13% of sALS patients, with a significant increase in cases versus controls.
• Highlights the need for improved diagnostic algorithms for variants of unknown significance and better patient counseling resources for ALS genetic testing.