Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL
Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL
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DOI：
10.1002/acn3.344
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发表时间：
2016-11-01
影响因子：
5.3
通讯作者：
Oberstein, Saskia A. J. Lesnik
中科院分区：
文献类型：
--
作者：
Rutten, Julie W.;Dauwerse, Hans G.;Oberstein, Saskia A. J. Lesnik
目的：确定外显子组聚集联盟（ExAC）数据库中60，706个外显子组中独特的EGFr半胱氨酸改变NOTCH 3突变的频率。研究方法：询问ExAC是否存在常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）的特征性突变，即导致NOTCH 3的34个EGFr结构域之一发生半胱氨酸氨基酸变化的突变。在一个独立的荷兰CADASIL患者队列中，使用量化的MRI病变对ExAC数据预测的基因型-表型相关性进行了检测。荷兰CADASIL登记处调查了70岁以上的少症状个体。结果：我们在ExAC中确定了206个EGFr半胱氨酸改变NOTCH 3突变，总患病率为3.4/1000。超过一半的独特突变先前已在CADASIL患者中报道。尽管存在明显的重叠，但ExAC中的突变分布与报告的CADASIL患者不同，因为ExAC中的突变主要位于EGFr结构域1-6之外。在一个独立的荷兰CADASIL队列中，我们发现EGFr结构域7-34突变的患者比EGFr结构域1-6突变的患者具有显著更低的MRI病变负荷。解释：EGFr半胱氨酸改变NOTCH 3突变的频率比基于CADASIL患病率估计的预期高100倍。这挑战了目前的CADASIL疾病模式，并表明某些突变可能更频繁地导致更温和的表型，甚至可能在临床上无法识别。我们的数据表明，位于EGFr结构域1-6的突变的个体倾向于更严重的“经典”CADASIL表型，而EGFr结构域1-6以外的突变的个体可以保持很少的症状，直到他们的第八个十年。
Objective: To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database. Methods: ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years. Results: We identified 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1-6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7-34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1-6. Interpretation: The frequency of EGFr cysteine altering NOTCH3 mutations is 100-fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1-6 are predisposed to the more severe "classical" CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1-6 can remain paucisymptomatic well into their eighth decade.