TARDBP pathogenic variants in patients with amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease phenotypes.

Abstract

Genetic, cerebrospinal fluid and histopathological studies have highlighted the importance of TDP-43 (the protein product of the TARDBP gene) in the pathophysiology of neurodegeneration. Specifically, TDP-43 pathology has been associated with Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and, lately, Alzheimer's Disease (AD). Here we searched for TARDBP pathogenic variants in a cohort of Greek patients with AD, FTD, ALS or FTD/ALS. A total of 192 patients were included in the study. These participants were 1) referred for testing to the Neurology/Neurogenetics Laboratory of the University of Crete, 2) identified through the Cretan Aging Cohort (CAC), 3) referred to the 1st Department of Neurology of the National and Kapodistrian University of Athens at Eginition Hospital, Athens, Greece. Of these, 95 were clinically characterized as AD, 45 as FTD, 44 as ALS and 8 as FTD-ALS. Patients' DNA samples were analyzed through Whole Exome Sequencing (WES). Subsequently, we analyzed WES data for the presence of TARDBP pathogenic variants. All TARDBP pathogenic variants identified were verified by Sanger sequencing. We found three different TARDBP pathogenic variants in five apparently unrelated patients, two of whom had a family history of dementia or ALS. Two of the five patients, an 80-year-old male and a 82-year-old female, members of the CAC, were initially diagnosed as suffering from late-onset AD on the basis of their clinical presentation. Both were found to harbor the p.Ile383Val (c.1147A>G) TARDBP variant. The same variant had been found in another patient, also from Crete, presenting with a combined FTD/ALS phenotype. In addition, in 2 patients with pure ALS, we found the p.Met337Val (c.1009A>G) and the p.Asn352Ser (c.1055A>G) TARDBP pathogenic variants, respectively. Our analyses unraveled five patients with pathogenic TARDBP variants presenting with heterogeneous phenotypes, namely apparent late-onset AD, FTD/ALS and pure ALS phenotypes. Our findings further expand the phenotypic variability of the TARDBP gene variants and draw attention to the possibility that patients diagnosed with possible typical AD could harbor pathogenic TARDBP variants. Furthermore, our study showed that TARDBP pathogenic variants are a rather frequent cause of dementia in the Greek population.