Abstract：
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.
摘要：
遗传性出血性毛细血管扩张症（HHT），也被称为Rendu-Osler-Weber病,是一种显性遗传性血管疾病。临床诊断基于库拉索岛标准，ENG和ACVRL1基因的致病变异是大多数HHT病例的原因。根据法国国家基因组医学计划的建议，选择了四个具有阴性靶向基因面板并由多学科团队选择的家族，并进行了全基因组测序。通过标准分子细胞遗传学分析(FISH)确认结构变异。在两个明确诊断为HHT的家庭中，我们发现了9号染色体的两个不同的副中心倒位，都破坏了ENG基因。这些倒置被认为是患者HHT表型的致病原因。这是首次报道结构变化导致HHT。由于这样的平衡事件经常被基于外显子的测序错过(面板，exome),结构变异可能是导致HHT的原因。对于明确诊断为HHT且未发现致病性致病性变异的患者，可以建议进行基因组测序以检测这些事件。
