PURPOSE CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7-34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7-34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. METHODS Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1-6 pathogenic variant or an EGFr 7-34 pathogenic variant. The frequencies of NOTCH3 EGFr 1-6 and EGFr 7-34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. RESULTS CADASIL patients with an EGFr 1-6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7-34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1-6 pathogenic variant, whereas EGFr 7-34 pathogenic variant strongly predominate in the population. CONCLUSION NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7-34 pathogenic variant predisposing to a later onset of stroke and longer survival.

中文翻译：

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NOTCH3 致病性变异位置对 CADASIL 疾病严重程度的影响：与 EGFr 7-34 致病性变异相比，NOTCH3 EGFr 1-6 致病性变异与更严重的表型和更低的存活率相关。

目的 CADASIL 是一种小血管疾病，由 NOTCH3 蛋白的 34 个表皮生长因子样重复 (EGFr) 结构域之一的半胱氨酸改变致病性变异引起。我们最近发现 EGFr 结构域 7-34 中的致病变异在普通人群中具有出乎意料的高频率 (1:300)。我们假设 EGFr 7-34 致病性变异更频繁地导致更温和的表型，从而解释了 CADASIL 疾病变异性的重要部分。方法 比较了 664 名具有 NOTCH3 EGFr 1-6 致病性变异或 EGFr 7-34 致病性变异的 CADASIL 患者的首次卒中年龄、存活率和白质高信号量。在基因组聚合数据库中的个体和 CADASIL 患者之间比较了 NOTCH3 EGFr 1-6 和 EGFr 7-34 致病性变异的频率。结果 EGFr 1-6 致病性变异的 CADASIL 患者中风发病比 EGFr 7-34 致病性变异的患者早 12 年，存活率更低，白质高信号体积更大。在确诊的 CADASIL 患者中，70% 具有 EGFr 1-6 致病性变异，而 EGFr 7-34 致病性变异在人群中占主导地位。结论 NOTCH3 致病性变异位置是 CADASIL 疾病严重程度的最重要决定因素，EGFr 7-34 致病性变异易导致卒中发病较晚和生存期更长。而 EGFr 7-34 致病性变异在人群中占主导地位。结论 NOTCH3 致病性变异位置是 CADASIL 疾病严重程度的最重要决定因素，EGFr 7-34 致病性变异易导致卒中发病较晚和生存期更长。而 EGFr 7-34 致病性变异在人群中占主导地位。结论 NOTCH3 致病性变异位置是 CADASIL 疾病严重程度的最重要决定因素，EGFr 7-34 致病性变异易导致卒中发病较晚和生存期更长。