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

• DOI: 10.1126/sciadv.ade2044
• Publication Date: 2023-05-05T17:58:17Z
• Authors: Lyndal Henden; Liam G. Fearnley; Natalie Grima; Emily P. McCann; Carol Dobson-Stone; Lauren Fitzpatrick; Kathryn Friend; Lynne Hobson; Sandrine Chan Moi...; Dominic B. Rowe; Susan D’Silva; John B. Kwok; Glenda M. Halliday; Matthew C. Kiernan; Srestha Mazumder; Hannah C. Timmins; Margaret Zoing; Roger Pamphlett; Lorel Adams; Melanie Bahlo; Ian P. Blair; Kelly L. Williams
• Keywords: C9ORF72; Tandem

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, polymerase chain reaction validation to assess 21 disease-associated whole-genome sequencing data from 608 patients with ALS, 68 FTD, 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds rare STRs. Excluding C9orf72 expansions, 17.6% clinically diagnosed ALS FTD cases had at least one expanded STR reported be pathogenic or intermediate another disease. identified validated 162 disease-relevant (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy (DM1)], CNBP (DM2), FMR1 (fragile-X disorders). Our findings suggest clinical pathological pleiotropy disease genes highlight their importance FTD.