Abstract：
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers−Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders.
摘要：
脆性X综合征（FXS）是智力障碍最常见的遗传原因，也是仅次于唐氏综合征的第二大常见原因。FXS是一种X连锁疾病，由于FMR1基因CGG三联体重复的完全突变，编码一种在突触发生和维持细胞外基质相关蛋白功能中至关重要的蛋白，正常神经元和结缔组织（包括胶原蛋白）发育的关键。除了神经精神和行为问题，患有FXS的个体表现出暗示结缔组织疾病的身体特征，包括皮肤松弛和关节松弛，扁平足,疝气和二尖瓣脱垂.扰乱的胶原蛋白会导致过度活动，过度伸展的皮肤和组织脆性与肌肉骨骼，心血管,免疫和其他器官受累，如结缔组织遗传性疾病，包括Ehlers-Danlos综合征。最近,FMR1前突变重复扩增或携带者状态已在有结缔组织疾病相关症状的个体中报道。我们使用由大约75个基因组成的结缔组织疾病基因小组的下一代测序（NGS）检查了一组具有结缔组织疾病特征的女性，这些女性具有提供遗传服务的特征。在那些NGS正常检测结缔组织疾病的女性中，然后使用CGG重复扩增研究分析FMR1基因.发现39位女性中有3位以1：13的比例具有灰色区域或中间等位基因，与以1：66的比例代表普通人群的新生女性相比，明显更高（p＆lt;0.05）。首次报道的女性结缔组织受累与中间或灰色区域等位基因的这种关联将需要更多的研究，以了解大小变异如何直接影响FMR1基因功能和蛋白质或与结缔组织疾病相关的其他易感基因的关系。
