2022.10.26
High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease
Uemura M1, Hatano Y1, Nozaki H2, Ando S1, Kondo H3, Hanazono A4, Iwanaga A5, Murota H5, Osakada Y6, Osaki M7, Kanazawa M1, Kanai M8, Shibata Y9, Saika R9, Miyatake T10, Aizawa H11, 12, Ikeuchi T13, Tomimoto H14, Mizuta I15, Mizuno T15, Ishihara T1, Onodera O1.
1Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University.
2Department of Medical Technology, Graduate School of Health Sciences, Niigata University.
3Department of Neurology, Anjo Kosei Hospital.
4Division of Gastroenterology, Hepato-biliary-pancreatology and Neurology, Akita University.
5Department of Dermatology, Nagasaki University.
6Department of Neurology, Okayama University.
7Cerebrovascular Medicine, Steel Memorial Yawata Hospital.
8Department of Neurology, National Hospital Organization Takasaki General Medical Center.
9Department of Neurology, Japanese Red Cross Osaka Hospital.
10Department of Neurology, Saiki Hospital.
11Department of Neurology, Tokyo Medical University.
12Department of Neurology, Tokyo National Hospital.
13Department of Molecular Genetics, Brain Research Institute, Niigata University.
14Department of Neurology, Mie University.
15Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
Abstract
Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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.
Keywords: CEREBROVASCULAR DISEASE; GENETICS; STROKE; VASCULAR DEMENTIA.
*Reprinted under the terms of the Creative Commons Attribution License (CC BY).
