Syx Delfien, Symoens Sofie, Steyaert Wouter, De Paepe Anne, Coucke Paul J, Malfait Fransiska
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Dis Markers. 2015;2015:828970. doi: 10.1155/2015/828970. Epub 2015 Oct 4.
Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition.
关节过度活动是普通人群中常见的、大多为良性的表现。然而，在一部分个体中，它会引发一系列临床问题，主要影响肌肉骨骼系统。关节过度活动常表现为一种家族性特征，并且与几种遗传性结缔组织疾病相关，包括埃勒斯-当洛综合征（EDS-HT）的过度活动亚型或良性关节过度活动综合征（BJHS）。这些遗传性疾病为研究关节过度活动的遗传基础提供了独特的模型。然而，这些研究在很大程度上受到临床表现的巨大变异性以及许多家族中往往模糊的遗传模式的阻碍。在此，我们对一个具有常染色体显性EDS-HT表型的独特三代家族进行了全基因组连锁扫描，并在8号染色体p22 - 8p21.1区域确定了一个连锁区间，最大两点LOD得分为4.73。随后的全外显子组测序揭示在候选区域内的LZTS1基因中存在一个独特的错义变异。对230例EDS-HT/BJHS患者的后续分析又鉴定出另外三个罕见变异。这是首次报道的对EDS-HT家族进行的全基因组连锁分析，从而为确定这种疾病的一个新致病基因提供了契机。
