PT  - JOURNAL ARTICLE
AU  - Jennifer Roggenbuck
AU  - Marilly Palettas
AU  - Leah Vicini
AU  - Radha Patel
AU  - Adam Quick
AU  - Stephen J. Kolb
TI  - Incidence of pathogenic, likely pathogenic, and uncertain ALS variants in a clinic cohort
AID  - 10.1212/NXG.0000000000000390
DP  - 2020 Feb 01
TA  - Neurology Genetics
PG  - e390
VI  - 6
IP  - 1
4099  - http://ng.neurology.org/content/6/1/e390.short
4100  - http://ng.neurology.org/content/6/1/e390.full
SO  - Neurol Genet2020 Feb 01; 6
AB  - Objective To determine the incidence of amyotrophic lateral sclerosis (ALS) genetic variants in a clinic-based population.Methods A prospective cohort of patients with definite or probable ALS was offered genetic testing using a testing algorithm based on family history and age at onset.Results The incidence of pathogenic (P) or likely pathogenic (LP) variants was 56.0% in familial ALS (fALS); 11.8% in patients with ALS with a family history of dementia, and 6.8% in sporadic ALS (p < 0.001). C9orf72 expansions accounted for the majority (79%) of P or LP variants in fALS cases. Variants of uncertain significance were identified in 20.0% of fALS cases overall and in 35.7% of C9orf72-negative cases. P or LP variants were detected in 18.5% of early-onset cases (onset age <50 years); the incidence of P or LP variants was not significantly different between family history types in this group.Conclusions Our data suggest that the incidence of P and LP variants in genes other than C9orf72 is lower than expected in Midwestern fALS cases compared with research cohorts and highlights the challenge of variant interpretation in ALS. An accurate understanding of the incidence of pathogenic variants in clinic-based ALS populations is necessary to prioritize targets for therapeutic intervention and inform clinical trial design.ACMG=American College of Medical Genetics; ALS=amyotrophic lateral sclerosis; dALS=patients with ALS with a family history of dementia; fALS=familial ALS; LP=likely pathogenic; P=pathogenic; sALS=sporadic ALS; VUS=variant of uncertain significance