Background: Estimated frequencies of amyotrophic lateral sclerosis (ALS)-associated gene variants have largely come from case series, which may be influenced by variation in genetic testing and access, particularly among apparently sporadic ALS (sALS) cases.
Objectives: To estimate frequencies of C9orf72, SOD1, TARDBP, and FUS variants among people with ALS.
Methods: Publications up to October 20, 2024 were identified through a published systematic review (Zou 2017) and an updated literature search. Pooled frequencies were calculated using random effects meta-analysis stratified by study design and region. Median estimates were reported when heterogeneity was high (I2≥90%) or strata included ≤ 2 studies.
Results: Of 5,512 studies screened, 138 met inclusion criteria. Compared to case series, population-based studies reported lower frequencies for SOD1 (2.3% vs. 4.0%) and FUS (0.9% vs. 1.3%), but higher for C9orf72 (8.1% vs. 6.2%) and TARDBP (1.4% vs. 1.3%) variants. Among population-based studies, frequencies in cases of ALS with known family history (fALS) were 28.8% for C9orf72, 5.3% for SOD1, 8.5% for TARDBP, and 2.8% for FUS and frequencies in apparently sALS cases were 4.5% for C9orf72, 0.5% for SOD1, 0.9% for TARDBP, and 0.6% for FUS. Population-based studies were lacking in APAC, Middle East/North Africa, and Sub-Saharan Africa. Frequencies were higher in population-based studies in Europe compared to North America for C9orf72 (8.5% vs 7.5%), SOD1 (2.5% vs. 1.9%), and TARDBP (1.4% vs 0.9%), but not FUS (0.7% vs 1.0%). The US ALS Identified program represents the largest ALS sample (7,483 people).
Conclusions: Estimated frequencies of C9orf72, SOD1, TARDBP, and FUS variants among people with apparently sALS underscore the need for broad access to genetic counseling and testing for diagnosis and genetically targeted therapies. Mutation frequencies varied by region, though population-based studies are lacking in many geographies and are needed to better characterize the genetic architecture of ALS.