Short tandem repeat expansions in patients with neurodegenerative dementia

We used ExpansionHunter (EH) to assess 22 neurodegenerative disease-associated STRs in whole-genome sequencing (WGS) data from 1568 patients with neurodegenerative dementia, and 1522 cognitively normal controls. Repeat primed-polymerase chain reaction (RP-PCR) was performed to validate EH calls that exceeded the intermediate thresholds of STR. We also attempted to use ExpansionHunterDenovo (EHDn) to detect C9orf72 expansions missed by EH. 33 PCR-validated pathogenic expansions were identified in nine genes (C9orf72, ATXN8OS, NOTCH2NLC, HTT, FMR1, DMPK, AR, CACNA1A, and PPP2R2B) among 1,559 patients with NDD. Burden-based logistic regression analyses demonstrated that the presence of pathogenic STR expansions was significantly associated with NDD status. Additionally, intermediate-length TBP alleles showed a nominal enrichment in PSP compared with controls.