Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia.

Autor: Henden L; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., Fearnley LG; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia., Grima N; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., McCann EP; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., Dobson-Stone C; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia., Fitzpatrick L; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia., Friend K; SA Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia., Hobson L; SA Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia., Chan Moi Fat S; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., Rowe DB; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.; Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia., D'Silva S; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.; Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia., Kwok JB; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia., Halliday GM; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia., Kiernan MC; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.; Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia., Mazumder S; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia., Timmins HC; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia., Zoing M; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia., Pamphlett R; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.; Discipline of Pathology, The University of Sydney, Sydney, NSW 2050, Australia.; Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia., Adams L; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., Bahlo M; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia., Blair IP; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia., Williams KL; Macquarie University Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 May 05; Vol. 9 (18), pp. eade2044. Date of Electronic Publication: 2023 May 05.
DOI: 10.1126/sciadv.ade2044
Abstrakt: Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.
Databáze: MEDLINE