Intrafamilial clinical phenotypic heterogeneity with progranulin gene p.Glu498fs mutation

Abstract 

A patient with a progressive aphasia syndrome underwent progranulin gene (GRN) testing in light of a family history of early-onset dementia in two of her brothers, one of whom had been previously examined and had the phenotype of frontal variant frontotemporal dementia. The proband was found to have the p.Glu498fs mutation. This is only the second English family, and the fifth family overall, to be described with this GRN mutation. There was marked intrafamilial phenotypic heterogeneity with respect to age at onset and clinical presentation. The mechanisms underpinning this heterogeneity, as seen with other GRN mutations, are currently unknown. Since all GRN mutations lead to progranulin haploinsufficiency, other modifying factors, possibly genetic, are implicated.

Keywords: Diagnosis, GRN mutation, Heterogeneity, Phenotype, Progranulin