Purpose

In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO.

Methods

We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO.

Results

Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs).

Conclusion

The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

中文翻译：

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HTT CAG 束中 CAA 中断丢失的频率以及在降低的外显率范围内对亨廷顿病的影响。

目的

在一些亨廷顿病 (HD) 患者中，“中断丢失”(LOI) 变体消除了HTT CAG 重复区中的中断密码子，这导致了较早的发病年龄 (AOO)。这种影响的大小是不确定的，因为以前的研究包括很少的 LOI 携带者，而且这种变异也会导致 CAG 大小的错误估计。我们开发了一种快速 LOI 检测屏幕，可以在明显的 HD 患者中进行无偏频率估计。此外，我们将已发表的数据与新发现患者的临床数据相结合，以准确描述 LOI 对 AOO 的影响。

方法

我们开发了一种 LOI 检测聚合酶链反应 (PCR) 测定法，并对患者进行筛查以估计 LOI 变异的频率及其对 AOO 的影响。

结果

LOI 携带者 ( n  = 49) 的平均发病时间比基于诊断出的 CAG 大小的预期提前 20.4 年。在校正 CAG 大小低估后，该变异仍与 9.5 年前的发病有关。LOI 存在于 1.02% 的症状性 HD 患者和 32.2% 的症状性外显率降低 (RP) 范围患者 (36-39 CAG)。

结论

LOI 导致发病明显更早，比 CAG 长度预期的要长，特别是在具有 36-39 个 CAG 重复的人中。这种变异的检测对 HD 家族有影响，特别是对于那些在 RP 范围内的家族。