Determine the impact family history has on the diagnostic rates of C9ORF72 repeat expansion analysis and sequencing of 24 Amyotrophic Lateral Sclerosis (ALS) genes.

ALS is a progressive neurodegenerative disease of the upper and lower motor neurons. It is clinically related to frontotemporal dementia (FTD), as pathogenic variants can manifest as both disorders in one individual or as separate disorders in members of a single family. 100+ genes have been associated with ALS, but very few have been established as high yield.

Evaluate a cohort of 347 individuals (average age 59yrs; range 21-92) with a clinical suspicion of ALS and/or FTD, who provided information regarding family history and pursued C9ORF72 analysis and/or multi-gene sequencing.

A family history of ALS/FTD was reported in 166/347 individuals undergoing testing. C9orf72 analysis was completed for 293 individuals and positive for 20.5% of all individuals tested, 26.6% (37/139) of individuals with a family history, and 14.9% (23/154) of individuals without a family history. Multi-gene sequencing was completed for 180 individuals, which included 116 individuals with negative C9ORF72 analysis. Multi-gene sequencing was positive for 7.2% (13/180) of all individuals tested, 11.5% (9/78) of individuals with a family history, and 3.9% (4/102) of individuals without a family history. Diagnostic results were reported in 8/24 genes sequenced: FUS, MAPT, OPTN, SOD1, SQSTM1, TAF15, TARDBP, VCP.

Although positive yield was higher for individuals with a family history, those without still had a notable positive yield (14.9%), suggesting that C9ORF72 is a high yield gene and should be considered in all individuals. Yield for multi-gene sequencing was notably lower than C9ORF72 analysis (3.9-11.5%), regardless of family history. Possibly due to the later age of onset and lower positive rates associated with these genes. However, C9ORF72, and to some degree sequence analysis, has diagnostic utility regardless of family history.