High frequency of<i>HTRA1</i>AND<i>ABCC6</i>mutations in Japanese patients with adult-onset cerebral small vessel disease
Masahiro Uemura, Yuya Hatano, Hiroaki Nozaki, Shoichiro Ando, H. Kondo, Akira Hanazono, Akira Iwanaga, Hiroyuki Murota, Yosuke Osakada, Masato Osaki, Masato Kanazawa, Mitsuyasu Kanai, Yoko Shibata, Reiko Saika, Tadashi Miyatake, Hitoshi Aizawa, Takeshi Ikeuchi, Hidekazu Tomimoto, Ikuko Mizuta, Toshiki Mizuno, Tomohiko Ishihara, Osamu Onodera
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.