D004 Longitudinal somatic expansion of the CAG repeat in the HTT gene in blood DNA as a potential therapeutic biomarker
Year: 2024
Type: conference-abstract
Abstract: Background Somatic expansion of the HTT CAG repeat plays a pivotal role in HD onset. Therefore, drugs targeting somatic expansion are expected to be therapeutically beneficial. To this end, biomarkers capable of detecting an effect on the rate of somatic expansion would be desirable. Ideally, we would be able to detect effects on somatic expansion in neurons, but this remains technically challenging. Thus, we aimed to investigate longitudinal changes in somatic expansion in accessible peripheral blood cells in individuals inheriting longer CAG alleles with faster rates of somatic expansion. Aims To quantify changes in the length of the HTT CAG repeat length over time in the blood DNA of individuals inheriting > 47 CAG repeats. Methods We performed triplicate ultra-deep MiSeq sequencing of the HTT repeat in 1,490 annual blood DNA samples from 335 Enroll-HD participants inheriting 48 to 69 CAG repeats. Data were analysed using an improved bioinformatics pipeline, and somatic expansions quantified. Results The new pipeline resulted in more reads being aligned to the larger alleles, and higher somatic expansion ratios (SER). We were able to detect annual changes (increase in most patients) in SERs over time using this method. In general, patients with larger inherited alleles had higher SERs. Conclusions Somatic expansion of CAG repeats in blood DNA can potentially be used as a therapeutic biomarker. Accurate quantification of DNA and some technical improvements, such as increasing the DNA and reducing the PCR cycles, are recommended to decrease technical variance and sample sizes in clinical trials.
Institution: University of Glasgow
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373834