Dissecting the Clinical Heterogeneity and Genotype-Phenotype Correlations of Mutations: A Systematic Review.

Background: Microtubule-associated protein tau () mutations are one of the main causes of genetic Frontotemporal dementia (FTD) and are characterised by high clinical heterogeneity. A behavioural variant of FTD is the principal phenotype, but other rarer phenotypes are described, mostly reported as single cases. In this review, we provide an overview of the clinical phenotypes associated with mutations in order to define their characteristics and explore genotype-phenotype correlations.

Methods: We performed systematic bibliographic research on the Pubmed database, focusing on articles published between 1998 and 2022. We analysed the clinical phenotype of 177 patients carrying mutations, focusing on the rarest ones. We performed a narrative synthesis of the results.

Results: Regarding language phenotypes, the most frequent were the non-fluent variant and the semantic variant of Primary Progressive Aphasia (nfvPPA, svPPA), approximately in the same proportion. Almost 20% of the whole group of patients present a clinical phenotype belonging to the corticobasal syndrome-progressive supranuclear palsy (CBS-PSP) spectrum. While no clear genotype-phenotype correlation could be identified, some mutations were associated with a specific phenotype, while others gave origin to multiple clinical pictures and mixed phenotypes.

Conclusions: A high clinical heterogeneity exists in FTD associated with mutations without a clear phenotype-genotype correlation in most cases. However, some characteristics can be helpful to drive genetic testing. Deep phenotyping of patients, together with functional studies of single mutations, particularly those associated with atypical phenotypes, are necessary to better understand the biological mechanisms underlying this clinical variability.