Sequence Variants in Small CAG Repeat Expansions of the <i>HTT</i> Gene and Disease Onset and Progression in Huntington Disease

BACKGROUND AND OBJECTIVES: ) expansions beyond onset. METHODS: repeats. We used either clonal Sanger sequencing (in Vancouver) or short read sequencing (in Paris) to detect sequence variants. We compared age at onset (AO) and the ratio between reported and the Langbehn-predicted AO depending on the DNA sequence. We assessed the longitudinal progression of cognitive, motor, and functional scales over disease duration using linear mixed models and compared progression slopes according to the DNA sequence. RESULTS: < 0.001). Motor progression and cognitive decline were significantly faster in patients with a loss of the CAA and CCA interruptions (CAG-CCG LOI) compared with those harboring the canonical sequence. In addition, we identified 1 novel variant (CAG LOI-LO CCG) in 5 patients, leading to underestimation of 3 CAG repeats. DISCUSSION: In this large cohort, including DNA sequence and phenotypical data, the LOI variant showed a significant modifying effect on AO, motor, and cognitive disease progression. These findings, along with the identification of a novel variant, have important implications for genetic testing and counseling, especially for individuals with expansions close to cutoff ranges. In addition, they underscore the need to integrate the DNA sequence in the diagnostic process and revisit current onset prediction models.