Ehlers–Danlos syndrome (EDS), osteogenesis imperfecta (OI), and cutis laxa (CL) are three rare and heterogeneous connective tissue disorders. Patients with these syndromes have similar manifestations and unpredictable prognosis, making a misdiagnosis highly probable. Some of their subtypes are inherited in autosomal recessive patterns, so they are expected to be prevalent in populations like Iran, where consanguineous marriages are common. In the current work, a cohort of Iranian patients with overlapping phenotypes of the EDS/OI/CL and their mutation spectrum was defined. Based on this, in silico analysis was conducted to anticipate further probable genetic variations. Pathogenicity of EDS, OI, and CL variants in Iranian patients was evaluated using Web servers. A protein interaction network was created by String database and visualized using a Python-based library. The Iranome database was used to predict other genetic mutations in all reported genes of EDS, OI, and CL syndromes. In the EDS/OI/CL overlap phenotype, 32 variants in 18 genes have been involved. At least 59% of patients were from families with consanguineous marriages. Interaction analysis showed that COL1A1, COL1A2, CRTAP, LEPRE1, PLOD1, and ADAMTS2 have the most significant impact within the protein network of EDS/OI/CL overlap phenotype. Analyzing the Iranome database revealed 46 variants of EDS, OI, and CL genes potentially disease causing. The overlapping phenotype of EDS, OI, and CL syndromes requires genetic testing (e.g., whole-exome sequencing) to reveal respective variants, which helps to diagnose more accurately and manage the disease more effectively. Particularly in populations with high rates of consanguineous marriages, such as Iran, genetic screening plays a crucial role in premarital and prenatal counseling to prevent the transmission of these rare connective tissue disorders.

中文翻译：

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对伊朗人群中 Ehlers-Danlos、成骨不全和皮肤松弛重叠表型的突变谱进行计算机分析

埃勒斯-当洛斯综合征 (EDS)、成骨不全 (OI) 和皮肤松弛 (CL) 是三种罕见且异质的结缔组织疾病。患有这些综合征的患者具有相似的表现和不可预测的预后，极有可能误诊。其中一些亚型是以常染色体隐性遗传模式遗传的，因此预计它们会在像伊朗这样近亲结婚很常见的人群中流行。在当前的工作中，定义了一组具有 EDS/OI/CL 重叠表型及其突变谱的伊朗患者。在此基础上，进行了计算机分析以预测进一步可能的遗传变异。使用网络服务器评估伊朗患者中 EDS、OI 和 CL 变异的致病性。蛋白质相互作用网络由 String 数据库创建，并使用基于 Python 的库进行可视化。Iranome 数据库用于预测所有报告的 EDS、OI 和 CL 综合征基因中的其他基因突变。在EDS/OI/CL重叠表型中，涉及18个基因的32个变异。至少59%的患者来自近亲结婚家庭。相互作用分析表明，COL1A1、COL1A2、CRTAP、LEPRE1、PLOD1 和 ADAMTS2 在 EDS/OI/CL 重叠表型的蛋白质网络中具有最显着的影响。分析 Iranome 数据库揭示了 46 个可能导致疾病的 EDS、OI 和 CL 基因变异。EDS、OI 和 CL 综合征的重叠表型需要基因检测（例如全外显子组测序）来揭示各自的变异，这有助于更准确地诊断和更有效地管理疾病。特别是在伊朗等近亲结婚率较高的人群中，基因筛查在婚前和产前咨询中发挥着至关重要的作用，以防止这些罕见的结缔组织疾病的传播。