Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. In this article, we report a 40-year-old male patient who presented with a two-year history of progressive cognitive decline including impaired attention, memory, executive functions, and processing speed whose family history was strongly positive for young-onset ischemic stroke and memory impairment. His father, uncle, and grandfather died due to ischemic strokes and cognitive impairment (similar condition). A whole exome sequencing to the patient (proband II-1) revealed a novel heterozygous missense variant c.3009G>T, p.(Trp1003Cys) (chr19;15291625; hg19) in exon 19 of the NOTCH3 gene. Sanger sequencing was used to confirm the variant in other family members. This variant has not been described in the literature so far. The novel mutation described in the present study widened the genetic spectrum of NOTCH3-associated diseases, which will benefit studies addressing this disease in the future. CADASIL remains a disabling disorder leading to medical retirement in our patient due to late clinical presentation, lack of family history taking prior to joining the military, and lack of curative therapy. Further research for therapeutic options is needed including stem cell therapy .

中文翻译：

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沙特家族患有大脑常染色体显性动脉病伴皮质下梗死和白脑病的沙特家族中NOTCH3外显子19的新型杂合子变体。

伴有皮质下梗塞和白质脑病的脑常染色体显性动脉病（CADASIL； OMIM＃125310）是单基因家族性脑小血管疾病的最常见原因。它通常表现在成年中，具有高度可变的临床特征，包括偏头痛先兆，反复发作的短暂性脑缺血发作或缺血性中风，情绪障碍和进行性认知功能减退。它是由NOTCH3基因的突变引起的，该基因映射到19号染色体的短臂并编码表皮生长因子样重复序列。在本文中，我们报告了一名40岁的男性患者，该患者具有两年的进行性认知下降病史，包括注意力，记忆力，执行功能和处理速度减退，其家族病史对年轻发作的缺血性中风有很强的阳性作用和记忆障碍。他的父亲，叔叔和祖父死于缺血性中风和认知障碍（病情相似）。对患者的完整外显子组测序（先证者II-1）在NOTCH3基因的外显子19中发现了一个新的杂合错义变体c.3009G> T，p。（Trp1003Cys）（chr19; 15291625; hg19）。Sanger测序被用于确认其他家族成员中的变体。到目前为止，文献中尚未描述此变体。本研究中描述的新突变拓宽了与NOTCH3相关疾病的遗传谱，这将有益于今后解决该疾病的研究。由于临床表现较晚，由于缺乏入伍前的家族病史以及缺乏治愈性治疗，CADASIL仍然是导致我们患者医疗退休的致残疾病。