C004 Characterisation of the phenotype of sperm HTT-CAG variability in Huntington’s disease

<h3>Background</h3> Genetic anticipation is an incompletely understood, core characteristic of Huntington’s Disease (HD). It is denoted by the hastening of symptom onset of successive generations inheriting the HD mutation due to germline expansion of the CAG repeat, primarily occurring down the paternal line in HD. This process may lend to development of devastating juvenile onset disease. Those carrying larger alleles are thought to be at greater risk of genetic anticipation. <h3>Aims</h3> Characterise the phenotype of sperm CAG variability compared to blood instability and the influence of paternal age and inherited CAG length. <h3>Methods</h3> This study involves recruitment of male gene carriers of Stage 2 (HD-ISS, HD Integrated Staging System) and below to donate blood and semen samples. DNA extracted from blood and protocols for extraction of high-quality germline sperm DNA are being trialled. An initial sample of 31 men have been recruited. <h3>Results and Conclusions</h3> Pilot fragment analysis shows greater instability in sperm compared to blood, with those of larger inherited expansions having the greatest sperm instability and bias towards expansion. Future work will involve expanding recruitment to 120 men and using MiSeq sequencing to investigate germline instability to enable repeat variability to be characterised and the relationship between somatic instability in blood and germline instability in sperm to be determined. Exploratory genetic analysis will investigate the hypothesis of whether genetic modifiers of somatic instability also affect germline instability. Therapies are under development targeting somatic instability and it will be important to understand their potential effects on the germline.