To determine the clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS).

The discovery of ALS-associated pathogenic genetic variants have initiated development of genetically targeted therapies. With the expansion of genetic testing, the number of detected variants of uncertain significance (VUS) has increased, raising questions regarding their ALS pathogenicity, epigenetics, phenotype modification, and modulation of the phenotype of one mutation by another.

In this retrospective observational study, we chart reviewed 71 ALS patients at Keck USC ALS Center who had completed genetic testing in 2022-2023. All patients were tested for an ALS panel of 31 ALS-associated genes, CAG repeat expansion in ATXN2 gene and GGGGCC repeat expansion in C9orf72. Details of clinical presentation and family history (FH) were reviewed.

Out of the 71 patients, 2 tested positive for C9orf72 and 2 for ATXN2 repeat expansion. Among the 21 patients with mutant findings in the ALS panel, a total of 29 ALS-associated variants were identified with 6 patients having more than one. 1 was a reported pathogenic variant, 2 previously unreported but likely pathogenic variants, 4 suspected pathogenic VUS (3 reported and 1 unreported), 5 were reported VUS, and 17 were previously unreported VUS. Out of 71 patients, 3 had unknown FH and 11 had at least one first-degree relative either formally diagnosed or suspected to have ALS. Out of the 11, 2 had tested positive for C9orf72 repeat expansion, one for a reported VUS (NEFH c.443G>C), one for a reported VUS with suspected pathogenicity (UBQLN2 c.1481C>T), and rest without any identifiable mutant findings.

We found unreported variants of likely or suspected pathogenicity. Future studies should focus on clinical significance of these variants by studying genotype-phenotype correlation, FH, and relatives’ genetic testing.