RT Journal Article SR Electronic T1 Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e417 DO 10.1212/NXG.0000000000000417 VO 6 IS 3 A1 Mol, Merel O. A1 van Rooij, Jeroen G.J. A1 Brusse, Esther A1 Verkerk, Annemieke J.M.H. A1 Melhem, Shamiram A1 den Dunnen, Wilfred F.A. A1 Rizzu, Patrizia A1 Cupidi, Chiara A1 van Swieten, John C. A1 Donker Kaat, Laura YR 2020 UL http://ng.neurology.org/content/6/3/e417.abstract AB Objective To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48.Methods We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.Results Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case.Conclusions This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.AD=Alzheimer disease; CHIP=C-terminus of Hsp70-interacting protein; CI=cytoplasmic inclusion; DNS=diffuse nuclear staining; FTD=frontotemporal dementia; GATK=Genome Analysis Toolkit; NII=neuronal intranuclear inclusion; PSP=progressive supranuclear palsy; SCA=spinocerebellar ataxia; STR=short tandem repeat; WES=whole-exome sequencing; WGS=whole-genome sequencing