Abstract：
OBJECTIVE: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption (DOI) modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).
METHODS: We screened symptomatic HD participants from the UBC HD Biobank and five research sites for sequence variants. Following variant identification, we examined the clinical impact and frequency in the reduced penetrance range.
RESULTS: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of TMS by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of two symptomatic HD participants with diagnostic repeats below the pathogenetic range.
CONCLUSIONS: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cut-off ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.
METHODS: We screened symptomatic HD participants from the UBC HD Biobank and five research sites for sequence variants. Following variant identification, we examined the clinical impact and frequency in the reduced penetrance range.
RESULTS: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of TMS by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of two symptomatic HD participants with diagnostic repeats below the pathogenetic range.
CONCLUSIONS: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cut-off ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.
摘要：
目的：确定HTTCAG和CCG重复的中断丢失（LOI）和中断重复（DOI）修饰变体在亨廷顿病（HD）患者队列中的频率和临床影响。
方法：我们从UBCHDBiobank和五个研究位点筛选了有症状的HD参与者的序列变异。在变体识别之后，我们检查了外显率降低范围内的临床影响和频率.
结果：患有CAG-CCGLOI和CCGLOI变体的参与者在早期HD发作时具有相似的幅度，12.5年。序列变体表现出祖先特异性差异。具有CAG-CCGLOI变体的参与者的TMS进展也更快，每年1.9个单位。具有CAG-CCGLOI变体的有症状的参与者显示在降低的外显率范围内的富集。CAG-CCGLOI变体解释了两名有症状的HD参与者的发病，其诊断重复低于致病范围。
结论：我们的研究结果对CAG-CCGLOI变异的参与者有重要的临床意义，这些参与者在诊断截止范围附近接受了不准确的诊断。这些个体需要改进的诊断测试方法和临床管理。我们介绍了最大，最多样化的HTTCAG和CCG序列变异队列，并强调了它们在HD临床表现中的重要性。
方法：我们从UBCHDBiobank和五个研究位点筛选了有症状的HD参与者的序列变异。在变体识别之后，我们检查了外显率降低范围内的临床影响和频率.
结果：患有CAG-CCGLOI和CCGLOI变体的参与者在早期HD发作时具有相似的幅度，12.5年。序列变体表现出祖先特异性差异。具有CAG-CCGLOI变体的参与者的TMS进展也更快，每年1.9个单位。具有CAG-CCGLOI变体的有症状的参与者显示在降低的外显率范围内的富集。CAG-CCGLOI变体解释了两名有症状的HD参与者的发病，其诊断重复低于致病范围。
结论：我们的研究结果对CAG-CCGLOI变异的参与者有重要的临床意义，这些参与者在诊断截止范围附近接受了不准确的诊断。这些个体需要改进的诊断测试方法和临床管理。我们介绍了最大，最多样化的HTTCAG和CCG序列变异队列，并强调了它们在HD临床表现中的重要性。
