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Huntington’s disease (HD) is a neurodegenerative disease characterised by paternal anticipation in some families: disease severity worsens across generations due to expansion of the CAG repeat in the huntingtin (HTT) gene. Larger HTT-CAG repeat is associated with earlier onset of symptoms. HD progression is characterised by somatic HTT-CAG expansion in brain.This study aims to measure and characterise HTT-CAG repeat variability in germline (sperm) and somatic cells (blood) of people with HD, identify factors which influence this variability, and explore the potential of sperm as a biomarker of HTT-CAG repeat variability.We are conducting a prospective cohort study of 120 men aged 18-65 years with ≥40 CAG repeats. A germline-specific DNA extraction method has been developed. Targeted sequencing of the HTT repeat using MiSeq enables quantification of repeat variability. Preliminary findings indicate sperm exhibits greater HTT-CAG repeat variability than blood, and higher instability with greater baseline CAG size.This underscores the potential of semen as a valuable biofluid for investigating the genetic mechanisms that underscore genetic anticipation, and its potential as a biomarker of HTT-CAG repeat variability. Future research aims to investigate change in sperm-CAG variability at one-year follow-up, and to perform genetic analyses to identify variants that influence this.catrin.medicine@gmail.com