Rare genetic modifiers of Huntington’s disease reveal novel pathological mechanisms

Huntington’s disease (HD) is a progressive, untreatable neurodegenerative disorder that presents with a variable array of motor, psychiatric, cognitive and behavioural symptoms. HD is caused by a CAG repeat expansion in the HTT gene over a threshold length of 35 repeats, with longer repeats associated with earlier onset disease. Other genes, often associated with DNA repair, are known to modify HD onset. By exome sequencing 500 individuals with very early or late onset HD we identified cis and trans modifiers of HD onset. Cis modifiers involved the DNA sequence just 3’ to the CAG repeat: alteration of the canonical 5’-CAACAG-3’ to pure CAG was always associated with early onset HD (p = 2.77 x 10 -7 ) whereas extra CAA trinucleotides were associated with late onset HD (p = 3.48 x 10 -6 ). Significant trans modifiers included non-synonymous damaging variants in FAN1, a DNA repair nuclease. These variants were mostly associated with early onset HD and increased repeat expansion in a stem cell model of HD. Purified variant proteins showed significantly reduced DNA binding and nuclease activities in vitro . Overall these results link genetic modifiers in humans to a molecular mechanism of repeat expansion that represents an exciting novel therapeutic target. thomas.massey78@gmail.com