We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated.

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Department Hospital Clínic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

Center for Neuroscience and Cell Biology University of Coimbra Coimbra Portugal

Centre for Neurodegenerative Disorders Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Italy

Cyclotron Research Centre University of Liege and Memory Clinic CHU Liege Belgium

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Germany; Genome Biology of Neurodegenerative Diseases German Center for Neurodegenerative Diseases Tübingen Germany

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Germany; Neurodegeneration German Center for Neurodegenerative Diseases Tübingen Germany

Department of Neurology Memory Unit Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain and Center for Networked Biomedical Research into Neurodegenerative Disorders

Department of Neurology Neuromuscular Diseases Unit Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain and Center for Networked Biomedical Research into Rare Diseases

Department of Neurology University Hospitals Leuven Leuven Belgium; Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium; Laboratory of Neurobiology Center for Brain and Disease Research VIB Leuven Belgium

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy; IRCCS Don Gnocchi Florence Italy

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium; Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium; Department of Old Age Psychiatry and Memory Clinic University Hospitals Leuven Leuven Belgium

Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic; Department of Pathology 3rd Medical Faculty Charles University Prague Czech Republic

Department of Psychiatry and Psychotherapy Technische Universität München München Germany

Faculty of Medicine University of Lisbon Portugal

Fundació per la Recerca Biomèdica i Social Mútua de Terrassa Terrassa Barcelona Spain; Memory Disorders Unit Department of Neurology University Hospital Mutua de Terrassa Terrassa Barcelona Spain

Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium

Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology Antwerp University Hospital Edegem Belgium

Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology Antwerp University Hospital Edegem Belgium; Neurogenetics Group VIB UAntwerp Center for Molecular Neurology Antwerp Belgium

Neurodegenerative Brain Diseases Group VIB UAntwerp Center for Molecular Neurology Antwerp Belgium; Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium

Neurodegenerative Brain Diseases Group VIB UAntwerp Center for Molecular Neurology Antwerp Belgium; Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology Antwerp University Hospital Edegem Belgium

Neurological Tissue Bank of the Biobanc Hospital Clínic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

NeuroRARE Centre for Rare and Genetic Neurological and Neuromuscular Diseases and Neurogenetics Athens Greece

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