The value of a family history to distinguish monogenic from polygenic amyotrophic lateral sclerosis

The study examined the accuracy of family history in determining the genetic basis of amyotrophic lateral sclerosis (ALS). Using the APECS simulator, 1 million three-generation pedigrees were created and 5,431 ALS patients were analyzed, of which 16.4% had monogenic forms. The criterion for 'definite familial ALS' (2 or more relatives with ALS within two degrees of kinship) had only 31.1% sensitivity and incorrectly classified 10% of cases as monogenic. Sensitivity improved to 43.3% when frontotemporal dementia was included in the family history. Approximately 5.3% of patients with monogenic ALS had phenocopies with ALS in relatives. The results show that family history has limited accuracy in determining the genetic architecture of ALS. The study recommends routine genetic testing regardless of family history and systematic detection of distant relatives.