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Abstract

Huntington Disease (HD) is an autosomal dominant neurodegenerative trinucleotide repeat disorder caused by expansion of a polyglutamine-encoding CAG repeat sequence in the HTT gene. The length of the expanded CAG repeat inversely correlates with age at disease onset, but accounts for only 50-70% of individual variation in onset. Within recent years, several synonymous variants at the 3’ end of the CAG repeat have been identified as potential modifiers of HD onset. These variants affect codons which interrupt the CAG repeat and shorter downstream CCG repeat. Based on clinical data from HD patient cohorts, I show that one of these variants, the loss of CAG-CCG repeat interruption (CAG-CCG LOI variant), hastens disease onset by over 10 years. These variants are highly enriched in patients who become symptomatic with CAG repeat lengths in the reduced penetrance range, and were identified in two unrelated individuals who are symptomatic for HD despite having repeat lengths below the established pathogenic range. I have developed a clinically-applicable screening method to identify this variant, which is not detected by standard HD genetic testing, and propose that identification of the CAG-CCG LOI variant is crucial to accurate HD diagnosis. The mechanism by which the CAG-CCG LOI variant causes early onset is currently unknown, but somatic expansion of the CAG repeat, particularly in medium spiny neurons in the caudate, is hypothesized to be a key driver of HD pathogenesis. I show that the CAG-CCG LOI variant does not increase somatic expansion in the blood, and is associated with a reduced frequency of small somatic expansions in bulk caudate tissue. However, these variants may increase the frequency of larger expansions in the caudate and frontal cortex based on preliminary examination of a small number of HD brain tissues using a novel technique adapted from previous small-pool PCR methodology to enable quantification of large repeat expansions. Determining the mechanism of action of the CAG-CCG LOI variant may improve understanding of whether somatic expansion plays a role in HD pathogenesis, or shed light on novel biological pathways driving disease onset, which may provide new therapeutic targets for delaying or preventing Huntington Disease.