Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd. MS 4015, Kansas City, KS 66160, USA.
Fulgent Genetics, 4978 Santa Anita Ave., Temple City, CA 91780, USA.
Int J Mol Sci. 2022 Aug 13;23(16):9090. doi: 10.3390/ijms23169090.
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.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍病因，仅次于唐氏综合征。FXS 是一种 X 连锁疾病，由于 FMR1 基因的 CGG 三核苷酸重复完全突变，该基因编码一种对突触发生和维持细胞外基质相关蛋白功能至关重要的蛋白质，这对于正常神经元和结缔组织的发育至关重要，包括胶原蛋白。除了神经精神和行为问题外，FXS 患者还表现出提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。胶原紊乱导致过度活动、超伸展皮肤和组织脆弱，伴有肌肉骨骼、心血管、免疫和其他器官受累，如遗传性结缔组织疾病，包括埃勒斯-当洛斯综合征。最近，在具有结缔组织疾病相关症状的个体中报道了 FMR1 前突变重复扩增或携带者状态。我们使用包含大约 75 个基因的结缔组织疾病基因panel 的下一代测序（NGS），对有结缔组织疾病特征的女性队列进行了检查，这些女性因遗传问题就诊。在那些结缔组织疾病 NGS 检测正常的女性中，然后使用 CGG 重复扩增研究分析 FMR1 基因。在 39 名女性中，有 3 名女性的灰色区域或中间等位基因比例为 1:13，与代表一般人群的新生儿女性（比例为 1:66）相比，显著更高（p<0.05）。首次报道了结缔组织疾病女性的结缔组织受累与中间或灰色区域等位基因的相关性，需要更多的研究来确定大小变化如何直接或与其他参与结缔组织疾病的易感基因一起影响 FMR1 基因功能和蛋白。
