High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease. Issue 1 (19th October 2022)

• Record Type: Journal Article
• Authors: Uemura, Masahiro; Hatano, Yuya; Nozaki, Hiroaki; Ando, Shoichiro; Kondo, Hajime; Hanazono, Akira; Iwanaga, Akira; Murota, Hiroyuki; Osakada, Yosuke; Osaki, Masato; Kanazawa, Masato; Kanai, Mitsuyasu; Shibata, Yoko; Saika, Reiko; Miyatake, Tadashi; Aizawa, Hitoshi; Ikeuchi, Takeshi; Tomimoto, Hidekazu; Mizuta, Ikuko; Mizuno, Toshiki; Ishihara, Tomohiko; Onodera, Osamu
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 94:Issue 1(2023)
• Page Start: 74
• Page End: 81
• Publication Date: 2022-10-19
• Subjects: VASCULAR DEMENTIA -- GENETICS -- CEREBROVASCULAR DISEASE -- STROKE; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-329917
• Languages: English
• ISSNs: 0022-3050

Abstract

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.