M. Tusseau , M. Eyries , N. Chatron , F. Coulet , A. Guichet , E. Colin , B. Demeer , H. Maillard , J. Thevenon , C. Lavigne , V. Saillour , C. Paris , J.M. De Sainte Agathe , M. Pujalte , A. Guilhem , S. Dupuis-Girod , G. Lesca
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引用次数: 0
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.
遗传性出血性毛细血管扩张症(HHT)又称伦杜-奥斯勒-韦伯病,是一种显性遗传性血管疾病。临床诊断基于库拉索标准,ENG 和 ACVRL1 基因的致病变体是大多数 HHT 病例的病因。根据法国国家基因组医学计划(French National Plan for Genomic Medicine)的建议,一个多学科小组挑选了四个目标基因检测呈阴性的家族,并对其进行了全基因组测序。通过标准分子细胞遗传学分析(FISH)确认了结构变异。在两个确诊为 HHT 的家族中,我们发现了两个不同的 9 号染色体旁中心倒位,均破坏了 ENG 基因。这些倒位被认为是患者 HHT 表型的致病原因。这是首次报道结构变异导致 HHT。由于基于外显子的测序(panel、exome)往往会漏掉这种平衡事件,因此结构变异可能是导致HHT的一个未被充分认识的原因。建议对确诊为HHT且未发现致病变异的患者进行基因组测序以检测这些事件。
期刊介绍:
The European Journal of Medical Genetics (EJMG) is a peer-reviewed journal that publishes articles in English on various aspects of human and medical genetics and of the genetics of experimental models.
Original clinical and experimental research articles, short clinical reports, review articles and letters to the editor are welcome on topics such as :
• Dysmorphology and syndrome delineation
• Molecular genetics and molecular cytogenetics of inherited disorders
• Clinical applications of genomics and nextgen sequencing technologies
• Syndromal cancer genetics
• Behavioral genetics
• Community genetics
• Fetal pathology and prenatal diagnosis
• Genetic counseling.