Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next‐generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling.

中文翻译：

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第一例患有镶嵌NOTCH3基因致病变异的患者。未公开的马赛克及其检测的重要性

大脑皮层梗死和白脑病（CADASIL）是常染色体显性遗传性动脉疾病，是一种主要由NOTCH3基因的致病变异引起的遗传性小血管疾病。之前在NOTCH3中均未发表种系或体细胞镶嵌基因。CADASIL以常染色体显性方式遗传。只有很少的病例与从头致病变异有关。马赛克比以前认为的要普遍得多，因为马赛克变体经常不被公开。显然是从头变异，实际上可能是Sanger测序无法检测到的亲本拼接的结果，尤其是在低等级拼接的情况下。通过诸如深度靶向的下一代测序（NGS）分析之类的敏感工具进行的家长测试可以检测出通过Sanger测序测试的患者中未发现的中等或低水平镶嵌性病例。在这里，我们报告第一位患有马赛克的患者NOTCH3我们所知的基因致病变体；白细胞DNA中的等位基因分数低（13％）；病原体是他的两个女儿所继承的。在研究了他的两个患病女儿后，通过深度靶向NGS分析诊断出该患者。该报告强调了使用敏感工具（如深度靶向NGS分析）进行父母测试的重要性。马赛克检测对于诊断和适当的家庭遗传咨询非常重要。