These estimates improve upon previous data by utilizing a prospective population-based cohort design, placing the penetrance of neurodegenerative disease in C9orf72 HRE carriers lower than estimates from disease-enriched cohorts (>95% by age 80),1  ,13 but higher than indirect estimates (24%–33%).14,15 This further emphasizes the incomplete penetrance of C9orf72 HRE-associated disease, raising interesting aetiological questions regarding the genetic and environmental factors determining the individualized risk profile of each C9orf72 HRE carrier. The gene discussed is C9orf72; the disease is neurodegenerative disease.