Diness Birgitte Rode, Palmquist Rachel Nina, Norling Rikke, Hove Hanne, Bundgaard Henning, Hertz Jens Michael, Kondziella Daniel, Krieger Derk, Dunø Morten, Grønborg Sabine
Rigshospitalet, Copenhagen University Hospital, Department of Clinical Genetics, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Rigshospitalet, Copenhagen University Hospital, Department of Clinical Genetics, Denmark.
J Neurol Sci. 2020 Aug 15;415:116897. doi: 10.1016/j.jns.2020.116897. Epub 2020 May 13.
Heterozygous variants in smooth muscle alpha-actin gene (ACTA2) are the most frequent cause of autosomal dominant hereditary thoracic aortic disease (HTAD). Several genotype-phenotype associations have been described, including a severe multisystemic smooth muscle disorder associated with de novo ACTA2 p.R179 variants, characterized by highly penetrant and early onset vascular disease, involvement of smooth muscle cell (SMC)-dependent organs and a distinct cerebrovascular phenotype. Missense variants at position 258 (p.R258C and p.R258H) have also been reported to have a more severe presentation including an increased risk for aortic dissection and a high risk of stroke. It has previously been suggested that the cerebrovascular phenotype of patients with p.R258 variants could represent a mild presentation of the cerebrovascular phenotype associated with p.R179 variants. Here we report on a five generation HTAD family with the p.R258H variant and describe the cerebrovascular findings seen in three family members, to expand on the previously reported phenotype associated with variants at this codon.
平滑肌α-肌动蛋白基因（ACTA2）中的杂合变异是常染色体显性遗传性胸主动脉疾病（HTAD）最常见的病因。已经描述了几种基因型-表型关联，包括一种与新发ACTA2 p.R179变异相关的严重多系统平滑肌疾病，其特征为具有高度外显率和早发性血管疾病、平滑肌细胞（SMC）依赖性器官受累以及独特的脑血管表型。第258位的错义变异（p.R258C和p.R258H）也被报道具有更严重的表现，包括主动脉夹层风险增加和中风高风险。此前有人提出，携带p.R258变异患者的脑血管表型可能是与p.R179变异相关脑血管表型的轻度表现。在此，我们报告一个携带p.R258H变异的五代HTAD家族，并描述在三名家族成员中观察到的脑血管表现，以扩展此前报道的与该密码子变异相关的表型。
