High frequency ofHTRA1ANDABCC6mutations in Japanese patients with adult-onset cerebral small vessel disease

Author:

Uemura MasahiroORCID,Hatano YuyaORCID,Nozaki Hiroaki,Ando Shoichiro,Kondo Hajime,Hanazono Akira,Iwanaga Akira,Murota Hiroyuki,Osakada Yosuke,Osaki Masato,Kanazawa MasatoORCID,Kanai Mitsuyasu,Shibata Yoko,Saika Reiko,Miyatake Tadashi,Aizawa HitoshiORCID,Ikeuchi TakeshiORCID,Tomimoto Hidekazu,Mizuta Ikuko,Mizuno Toshiki,Ishihara Tomohiko,Onodera OsamuORCID

Abstract

BackgroundThis 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.MethodsThis 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 forNOTCH3andHTRA1, 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.ResultsGroup 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 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).ConclusionsMore than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

Funder

Takeda Science Foundation

Japan Agency for Medical Research and Development

Ministry of Education, Culture, Sports, Science and Technology

Japanese Ministry of Health, Labor, and Welfare, Japan

Japan Society for the Promotion of Science

Publisher

BMJ

Subject

Psychiatry and Mental health,Neurology (clinical),Surgery

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