A003 Longitudinal assessment of somatic expansions of the HTT CAG repeat in blood DNA

<h3>Background</h3> The Huntington’s Disease (HD) CAG repeat is somatically unstable. Although early human research focused on somatic expansions in post-mortem brains, studies have shown that somatic expansion can be detected in human blood DNA samples. <h3>Aims</h3> In the present study, we investigate longitudinal changes in somatic expansion ratio. <h3>Methods</h3> Blood DNA at 2 time points (separated on average by 8.03 years, SD = 2.00) from 363 individuals with HD (min inherited CAG = 37, max CAG = 59, median CAG = 43.5) were obtained from Enroll-HD. Somatic HTT expansions were quantified from blood DNA by amplicon MiSeq-sequencing of the HTT repeat. Somatic expansion ratio (SER = number of somatic expansion products/number of progenitor allele products) was used as a summary statistic of the quantity of somatic HTT expansions. <h3>Results</h3> Mean SER at baseline was .49 (SD = .39). At baseline, SER was correlated with inherited CAG length (r = .88, p &lt; .001) and, to a lesser degree, age (r = -.28, p &lt; .001). A longitudinal mixed-effects analysis was conducted to model change in SER. Duration of time between assessments interacted with CAG and base age in predicting SER. Based on the model results, low CAG values had limited somatic expansion while individuals with higher CAG values (especially CAG &gt; 45) tended to show greater somatic expansion. <h3>Conclusions</h3> Somatic expansion is detectable longitudinally in white blood cells, especially in high CAG participants. Further longitudinal analyses with multiple time points and shorter intervals are necessary to characterize these trajectories.