Monroe Glen R, Harakalova Magdalena, van der Crabben Saskia N, Majoor-Krakauer Danielle, Bertoli-Avella Aida M, Moll Frans L, Oranen Björn I, Dooijes Dennis, Vink Aryan, Knoers Nine V, Maugeri Alessandra, Pals Gerard, Nijman Isaac J, van Haaften Gijs, Baas Annette F
Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Am J Med Genet A. 2015 Jun;167(6):1196-203. doi: 10.1002/ajmg.a.36997. Epub 2015 Apr 2.
Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.
埃勒斯-当洛综合征（EDS）有多种不同形式，具有特定的表型和相关基因。由COL3A1基因杂合突变引起的血管型EDS，其特征是血管脆弱，在年轻时发生灾难性血管事件的风险很高。由COL5A1或COL5A2基因杂合突变引起的经典型EDS，其特征是皮肤脆弱、过度伸展以及关节松弛。迄今为止，已有报道称4名确诊为COL5A1突变的无关经典型EDS患者发生了血管破裂。我们描述了一位母亲及其两个儿子出现类似血管型EDS表型的家族性病例，他们均在早年死于动脉破裂。对先证者进行诊断性桑格测序未能检测到COL3A1、COL1A1、COL1A2、TGFBR1、TGFBR2、SMAD3和ACTA2基因的异常。接下来，使用针对与血管疾病相关的554个基因的下一代测序方法（血管基因组计划）对先证者的DNA进行分析。检测到COL5A1基因存在一种新的杂合突变，导致三螺旋结构域C末端的一个关键甘氨酸被替代（NM_000093.4:c.4610G>T；p.Gly1537Val）。该突变也存在于从先证者兄弟的尸检材料中分离出的DNA中。没有获得母亲的材料，但在她的父母、兄弟姐妹以及她儿子的父亲中排除了该突变，这表明COL5A1突变是在母亲的基因组中从头发生的。总之，我们报告了由COL5A1突变引起的致命性动脉事件的家族性病例。
