Aberrant Short Tandem Repeats: Pathogenicity, Mechanisms, Detection, and Roles in Neuropsychiatric Disorders

Abstract

Short tandem repeat (STR) sequences are highly variable DNA segments that significantly contribute to human neurodegenerative disorders, highlighting their crucial role in neuropsychiatric conditions. This article examines the pathogenicity of abnormal STRs and classifies tandem repeat expansion disorders(TREDs), emphasizing their genetic characteristics, mechanisms of action, detection methods, and associated animal models. STR expansions exhibit complex genetic patterns that affect the age of onset and symptom severity. These expansions disrupt gene function through mechanisms such as gene silencing, toxic gain-of-function mutations leading to RNA and protein toxicity, and the generation of toxic peptides via repeat-associated non-AUG (RAN) translation. Advances in sequencing technologies—from traditional PCR and Southern blotting to next-generation and long-read sequencing—have enhanced the accuracy of STR variation detection. Research utilizing these technologies has linked STR expansions to a range of neuropsychiatric disorders, including autism spectrum disorders and schizophrenia, highlighting their contribution to disease risk and phenotypic expression through effects on genes involved in neurodevelopment, synaptic function, and neuronal signaling. Therefore, further investigation is essential to elucidate the intricate interplay between STRs and neuropsychiatric diseases, paving the way for improved diagnostic and therapeutic strategies.