Sangeerthana Rajagopal
Huntington’s disease (HD) is a monogenic, CAG repeat expansion disorder presenting with cognitive, psychiatric and movement problems. Alleles of >35 CAG repeats are pathogenic. CAG repeats expand in somatic cells, particularly striatal medium-spiny neurons during a gene carrier’s lifetime. HD is slowly progressive, driven by CAG expansion in these cells which eventually leads to neuronal dysfunction and cell death manifesting as clinical motor symptom onset after decades. Inheriting a larger CAG expansion causes earlier symptom onset as the repeat accelerates toward the toxic threshold more quickly.
Genetic anticipation, earlier symptom onset in successive generations, is a central HD characteristic that is due to germline CAG expansion, which occurs predominantly during paternal transmission. Previous studies investigating sperm DNA showed CAG length variability in the sperm population using capillary electrophoresis. Next-generation sequencing methods are yet to be employed to investigate CAG sequence composition and variants to reliably quantify and understand germline CAG variation.
This study aims to characterise CAG variability in sperm and the contribution of paternal age, inherited CAG and genetic modifiers to the rate of CAG expansion. The study involves the prospective collection of blood and semen samples from male HD mutation carriers. Five sites across the UK are now recruiting with 112 participants consented and 97 men having provided a semen sample. A protocol for remote semen collection and sperm-specific DNA extraction has been established to collect samples and to isolate germline DNA. Data will be presented comparing different sperm DNA extraction methods and capillary electrophoresis versus MiSeq sequencing.
