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INTRODUCTION: Patients with familial early‐onset dementia (EOD) pose a unique opportunity for gene identification studies. METHODS: We present the phenotype and whole‐exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild‐type and mutant protein of the final candidate. RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss‐of‐function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases. Highlights: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early‐onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease.TRIM25 protein studies support that the mutation exerts its effect through loss of function.TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration.The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research. [ABSTRACT FROM AUTHOR]

Background: Patients with early‐onset dementia (EOD) often have a high genetic burden, and EOD kindreds with an autosomal dominant pattern of inheritance (ADPI) are particularly powerful for gene identification studies. Methods: We present the clinical phenotype and a whole‐exome sequencing (WES) study of a Spanish EOD family with ADPI, including five affected and two unaffected siblings. The proband case was negative for mutations in a Next Generation Sequencing panel of genes associated with neurodegenerative dementias. Candidate pathogenic mutations were prioritized according to frequency in population databases, impact/pathogenicity scores, and segregation (including a disease‐free second branch of the family). Final candidate genes were also examined in a set of Spanish‐origin FTD cases (n=583) and controls (n=493), plus in a Belgian WES dataset of AD (n=236) and FTD (n=269) cases. Results: Affected siblings had an average disease onset of 60.2 years (range 56‐63 years). Two had a behavioral rather than an amnestic phenotype, developing some psychotic features and significant parkinsonism after treatment with risperidone. However, CSF biomarkers in one patient were indicative of an AD pathology. WES was conducted in four affected and one unaffected siblings (all of them APOEε 4,4). Variant prioritization pointed to 16 candidate variants, including three loss of function variants, two in‐frame deletions, and 11 missense. Additional genetic analysis of another unaffected sibling, a fifth affected sibling with incipient disease, plus four unaffected relatives from the second branch narrowed the list to two candidate genes: TRIM25 (p.C186*, CADD score 36) and EEA1 (p.V693A, CADD 18.2). TRIM25 is a cytoplasmic protein that functions as an ubiquitin E3 ligase and is involved in the innate immune response, while EEA1 is an endosomal trafficking protein. Potentially pathogenic (CADD>20) rare variants were found in the studied populations in EEA1 (0,7‐3,8%; Spanish‐Belgian) and TRIM25 (0‐0,7%). All except one were missense variants of uncertain significance. Importantly, in TRIM25 which is highly intolerable for loss of function mutations, we identified one additional nonsense mutation in TRIM25 in a frontal‐type dementia case. Conclusion: We conclude that in this EOD family, the nonsense mutation in TRIM25 is the most likely causal mutation. [ABSTRACT FROM AUTHOR]

Background: Genetic studies in frontotemporal dementia (FTD) have identified multiple genes linked to the disease, yet explain only 30% of the patients. Identification of genetic causes in the remaining inherited cases is needed to elucidate the molecular biology of disease development, and thereby to pinpoint novel targets for therapeutic applications. Multiple lines of evidence have demonstrated disruption of the endo‐lysosomal pathway (ELP) in dementia. Here, we aimed to search for novel FTD genes in the ELP through rare variant association analysis. Method: We applied weighted protein‐protein interaction (PPI) network mapping using 66 dementia‐associated genes (FTD, Alzheimer disease and Lewy‐body dementia) as seed genes. From this 'Dementia interactome', we extracted brain expressed ELP associated genes consulting Gene Ontology, Reactome, GTEx and Braineac. Exome‐wide rare variant association was tested using SKAT‐O, CMC and Madsen‐Browning tests. Result: We generated whole exome sequencing data on 238 Belgian FTD patients and extracted exonic variants from whole genome sequencing data of 176 Belgian controls, obtained through collaboration with Project MinE (van der Spek et al., 2019). No genes passed exome‐wide significance level in the rare‐variant burden tests. Mapping ELP‐associated genes on the PPI network resulted in a list of 2.486 genes to be prioritized in our gene burden test results. As a result of this prioritization, 31 genes reached nominal significance. We are presently investigating those genes by incorporating their weight in the network (i.e. distance to known gene products and network topology), as genes with a higher weight are more likely contributors to disease development. Preliminary results suggest a role for vesicle‐mediated transport (GO:0016192) genes in FTD risk. Conclusion: Applying a tailored PPI network approach, we prioritized ELP‐associated genes as potential disease (risk/protective) genes for FTD. ELP candidate genes pointed towards a role for vesicle‐mediated transport in FTD pathogenesis. This prioritization approach increases the power needed for rare variant disease association. Furthermore, we present an accessible disease pathway‐based analysis pipeline that is applicable to different types of genetic studies (rare high‐penetrant vs common‐risk) and disease phenotypes and pathways of interest. [ABSTRACT FROM AUTHOR]