Basic Science and Pathogenesis

Area of Science:

• Genetics
• Neuroscience
• Genomic Medicine

Background:

• Pathogenic short tandem repeat (STR) expansions are known causes of neurodegenerative diseases such as frontotemporal dementia (FTD), Huntington's Disease (HD), and neuronal intranuclear inclusion disease (NIID).
• These STR-associated neurodegenerative dementias exhibit significant phenotypic and genetic heterogeneity.
• Limited data exists on STR contributions within large neurodegenerative dementia cohorts in China.

Purpose of the Study:

• To investigate the prevalence and contribution of 19 neurodegenerative disease-associated STRs in Chinese patient cohorts.
• To determine the diagnostic utility of STR expansion detection in various neurodegenerative dementias.

Main Methods:

• Whole-genome sequencing data from 928 Alzheimer's Disease (AD), 231 Progressive Supranuclear Palsy (PSP), 208 FTD, and 165 Dementia with Lewy Bodies (DLB) patients were analyzed.
• ExpansionHunter (EH) and ExpansionHunterDenovo (EHDn) were employed to detect STR expansions.
• Polymerase chain reaction (PCR) was used for validation of identified STR expansions.

Main Results:

• Pathogenic STR expansions were identified in FTD (C9orf72, HTT, Notch2NLC), AD (C9orf72, HTT, Notch2NLC, FMR1), and DLB (PPP2R2B, AR) cohorts.
• 12.5% of clinically diagnosed FTD cases and 7.36% of PSP cases harbored at least one expanded STR allele.
• Intermediate expansions were noted in PSP (TBP) and DLB (HTT) cohorts, indicating broader STR involvement.

Conclusions:

• STR expansions play a significant role in the etiology of diverse neurodegenerative dementias.
• The findings underscore the clinical and pathological pleiotropy of genes associated with neurodegenerative diseases.
• This study highlights the importance of STR analysis in diagnosing and understanding neurodegenerative dementias in the Chinese population.