A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathologic examination revealed massive accumulation of abnormally hyperphosphorylated, conformational, truncated tau at aspartic acid 421, ubiquitinated and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes), and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67 to 70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of the expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3, and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP and no pathologic expansion in C9ORF72. However, a novel rare heterozygous sequence variant(p.Q140H) of uncertain significance was identified in FUS in both siblings.