Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Emergency and Critical Care Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Am J Hypertens. 2020 Feb 22;33(2):190-197. doi: 10.1093/ajh/hpz151.
Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family.
Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations.
Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity.
Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.
高血压并短指（趾）畸形综合征（HTNB），又称 Bilginturan 综合征，是一种罕见的常染色体显性遗传疾病，其特征为严重的盐不依赖性高血压、身材矮小、短指（趾）畸形以及未经治疗者在 50 岁前因中风而死亡。本研究旨在鉴定导致 HTNB 并伴有椎动脉畸形的 PDE3A 突变，该家系来自中国。
采集所有受试者的外周血样以提取 DNA。采用下一代测序和 Sanger 测序进行 PDE3A 突变鉴定。对携带 PDE3A 突变的 HTNB 先证者进行了比较分析。
遗传分析发现 HTNB 先证者 PDE3A 基因 c.1346G>A 错义突变，导致 p.Gly449Asp 氨基酸改变，该突变位于高度保守结构域，不同生物信息学工具预测其为有害突变。共分离分析表明先证者从其父亲遗传了该突变。降压治疗对先证者有效。对携带 9 种不同 PDE3A 突变的 HTNB 先证者进行比较分析发现存在表型异质性。
遗传筛查可以显著提高 HTNB 患者的早期诊断率。本研究不仅增加了中国人群中 PDE3A 突变的谱，将 HTNB 患者的表型扩展至包括椎体畸形，而且提高了对 HTNB 发病机制的认识。我们强调了降压治疗和长期随访的重要性，以预防中风和不良心血管事件。
