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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related disorders, linked pathologically and genetically by the TAR DNA-binding protein-43 (TDP-43). Pathogenic variants in TARDBP encoding for TDP-43 have been described less frequently in FTD than in ALS, and clinicopathological studies are scarce.1 We previously observed a high frequency of the I383V variant in TARDBP in a Dutch cohort of FTD patients.2 Here, we provide further evidence for the pathogenicity of this variant and present its clinicopathological characteristics. We ascertained all FTD (n=13) and ALS patients (n=4) with the I383V variant (NM_007375.3: c.1147A>G, p.Ile383Val) in TARDBP from three university medical centres in the Netherlands (Amsterdam, Rotterdam and Utrecht), as identified by whole-exome or whole-genome sequencing in either clinical or research setting. Concurrent pathogenic variants in 20 other genes associated with ALS, FTD or other forms of dementia were excluded in all patients. Brain imaging (CT or MRI) was available for all FTD patients. Quantitative assessment of volume loss across lobar brain regions was performed in those patients with T1-weighted MRI images of sufficient quality (n=5), and compared with a gender-matched/age-matched reference population. Family histories were classified into adjusted Goldman categories, which were described previously.2 Additionally, we performed extensive genealogical research to investigate possible relatedness between the index patients. Brain autopsy and routine immunohistochemistry was performed for two FTD patients by the Netherlands Brain Bank. One patient (4M) was reported previously as M008015-001.1 Detailed information on the genetic, neuroimaging, genealogical and pathological analyses can be found in the1. ### Supplementary data [jnnp-2020-325150supp001.pdf] ### The variable clinical phenotype and reduced penetrance of the I383V variant All 13 FTD patients with the I383V variant in TARDBP presented with a combination of behavioural changes and semantic deficits. The diagnoses of semantic variant of primary progressive aphasia (svPPA) are intriguing since this is usually considered a sporadic disorder. One patient (4M) showed additional motor …

Tauopathies are a group of neurodegenerative diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), or frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) that are characterised by altered metabolism and deposition of the microtubule associated protein tau. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau). Discovery of silence and intronic mutations leading to increased 4R/3R ratio in FTDP-17 affected families revealed that a disbalance in 4R-tau and 3R-tau in favour of the 4R isoform is sufficient to cause neurodegeneration with personality disturbances, dementia and motor dysfunction. Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by involuntary movements, psychiatric symptoms and dementia that is caused by an expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene. HD thus belongs to the group of dominant trinucleotide repeat diseases that include many other CAG repeat disorders such as the spinocerebellar ataxias SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, dentatorubropallidoluysian atrophy (DRPLA) and spinobulbar muscular atrophy (SBMA) as well as the CUG repeat disorders SCA8 and myotonic dystrophy 1 (DM1). A key element in the pathogenesis of the latter is the binding of splicing factors by the mutant CUG transcript, thus leading to alternative splicing aberrations in multiple genes. Intriguingly, CAG repeats have recently been shown to mimic CUG repeats in the misregulation of alternative splicing. Since it has also been very recently reported that aberrant splicing contributes to the generation of the highly toxic short N-terminal species of HTT, it is conceivable that splicing alterations significantly contribute to HD pathogenesis. Here we aim to explore whether the neurodegeneration-causing increase in 4R/3R-tau mRNA ratio occurs in HD by performing quantitative RT-PCR from RNA extracted from striatum and cortex of HD and control subjects.