High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease.
High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease.
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DOI：
10.1136/jnnp-2022-329917
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发表时间：
2023-01
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影响因子：
--
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中科院分区：
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本研究旨在阐明日本成人型严重脑小血管病（mgCSVD）患者中单基因脑小血管病（mgCSVD）的频率和临床特征。本研究纳入了发病年龄≤55岁（第1组）或>55岁且有阳性家族史（第2组）的成人发作重度CSVD患者。在对NOTCH 3和HTRA 1进行常规基因检测后，对未确诊的患者进行全外显子组测序。根据基因检测的结果，患者被分为两组：单基因组和未确定组。比较两组患者的临床及影像学表现。第1组和第2组分别包括75名和31名患者。总共有30例患者有NOTCH 3突变，11例患者有HTRA 1突变，6例患者有ABCC 6突变，1例患者有TREX 1突变，1例患者有COL 4A 1突变，1例患者有COL 4A 2突变。在mgCSVD患者中，NOTCH 3、HTRA 1和ABCC 6基因突变的总频率为94.0%。在第1组中，第一亲属家族史、高血压和多发性腔隙性脑梗死（LI）的频率在两组之间有显著差异（单基因与未确定;第一亲属家族史，61.0%与25.0%，p=0.0015;高血压，34.1%与63.9%，p=0.0092;多个LI，87.8% vs 63.9%，p=0.0134）。超过90%的mgCSVD是通过筛查NOTCH 3、HTRA 1和ABCC 6诊断的。这三个基因的靶序列可以有效地诊断日本患者的mgCSVD。
This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan. This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests for NOTCH3 and HTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups. Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients had NOTCH3 mutations, 11 patients had HTRA1 mutations, 6 patients had ABCC6 mutations, 1 patient had a TREX1 mutation, 1 patient had a COL4A1 mutation and 1 patient had a COL4A2 mutation. The total frequency of mutations in NOTCH3, HTRA1 and ABCC6 was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134). More than 90% of mgCSVDs were diagnosed by screening for NOTCH3, HTRA1 and ABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.
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8.3
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