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

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.

Whole‐exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk

“…Mutations in this gene result in diseases of the immune system including Aicardi-Goutieres syndrome and other autoimmune-type diseases which can put subjects at a higher risk of ischemic stroke. Uemura 2023 investigating the prevalence of Mendelian stroke genes mutations in monogenic cerebral small vessel stroke patients aged 55 years or younger from a Japanese stroke registry identified a TREX1 pathogenic genetic variants in one stroke subject (Uemura et al 2023). A large Mendelian Stroke Consortium also identified pathogenic clinical variants in TREX1 (Grami et al 2020).…”

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

“…In recent years, increasing numbers of genes have been associated with cSVDs ( 8 – 18 ). Notably, mutations in four genes — NOTCH3 , HTRA1 (high-temperature requirement A serine peptidase 1), COL4A1 (collagen type IV α1), and COL4A2 — account for the vast majority of monogenic adult-onset cSVDs ( Table 1 ) ( 19 – 22 ). Among these monogenic forms, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by dominant missense mutations that alter the number of cysteines in one of the 34 EGF repeats in the extracellular domain of the NOTCH3 protein (NOTCH3 ECD ), is the most frequent ( 23 ).…”

Missense Variants in COL4A1/2 Are Associated with Cerebral Aneurysms: A Case Report and <span aria-describedby="tippy-31">Literature Review

“…Written informed consents were obtained from the patient (proband) and her mother. Genetic testing and exome sequencing (ES) were performed as described previously [7]. Briefly, genomic DNA was extracted from the proband's blood, and Sanger sequencing analysis was performed for NOTCH3 and HTRA1.…”