High frequency of <i>HTRA1</i> AND <i>ABCC6</i> mutations in Japanese patients with adult-onset cerebral small vessel disease.

Abstract

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 <i>NOTCH3</i> and <i>HTRA1</i>, 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 <i>NOTCH3</i> mutations, 11 patients had <i>HTRA1</i> mutations, 6 patients had <i>ABCC6</i> mutations, 1 patient had a <i>TREX1</i> mutation, 1 patient had a <i>COL4A1</i> mutation and 1 patient had a <i>COL4A2</i> mutation. The total frequency of mutations in <i>NOTCH3</i>, <i>HTRA1</i> and <i>ABCC6</i> 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 <i>NOTCH3</i>, <i>HTRA1</i> and <i>ABCC6</i>. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.