GRNmutation spectrum and genotype–phenotype correlation in Chinese dementia patients: data from PUMCH dementia cohort

Abstract

BackgroundMethodsTheGRNmutations, especially of the loss of function type, are causative of frontotemporal dementia (FTD). However, severalGRNvariants can be found in other neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease. So far, there have been over 300GRNmutations reported globally. However, the genetic spectrum and phenotypic characteristics have not been fully elucidated in Chinese population.The participants were from the dementia cohort of Peking Union Medical College Hospital (n=1945). They received history inquiry, cognitive evaluation, brain imaging and exome sequencing. The dementia subjects carrying the rare variants of theGRNwere included in this study. Those with the pathogenic or likely pathogenic variants of other dementia-related genes were excluded.Results14 subjects carried the rare variants ofGRN. They were clinically diagnosed with behavioural variant of FTD (n=2), non-fluent/agrammatic variant primary progressive aphasia (PPA, n=3), semantic variant PPA (n=1), AD (n=6) and mixed dementia (n=2). 13 rare variants ofGRNwere found, including 6 novel variants (W49X, S226G, M152I, A91E, G79E and A303S). The most prevalent symptom was amnesia (85.7%, 12/14), followed by psychiatric and behavioural disorder (78.6%, 11/14). In terms of lobar atrophy, temporal atrophy/hypometabolism was the most common (85.7%, 12/14), followed by parietal atrophy/hypometabolism (78.6%, 11/14).ConclusionThe novelGRNvariants identified in this study contribute to enrich theGRNmutation repertoire. There is phenotypic similarity and diversity among Chinese patients with theGRNmutations.