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目的 :临床上发现一组特殊病例,一个家族4代人中均发现有同一种神经肌肉性疾病的患者,症状具体表现为上肢肘关节有不同程度的伸直受限,下肢踝关节似马蹄样畸形,足部高弓畸形、无明显内翻内收现象。本研究拟通过全基因组测序,探讨其发病的致病基因及分子机制。方法:利用高通量测序技术,分别对患儿、具有相似症状的患儿父亲及健康母亲的血液样本进行全基因组测序。利用生物信息学分析筛选疾病相关基因突变,并进一步收集该家族中的其他患病及健康成员的血液样本,利用PCR技术进行验证。结果:生物信息学分析发现一系列突变基因,包括ANXA3基因突变[chr4,c.C820T(p.R274*)]、ATP6V1E2基因突变[chr2,c.G136A(p.V46M)]和HIST1H3A基因突变[chr6,c.C205T(p.Q69*)]等。基于家族更多成员血液样本的PCR实验结果进一步证实,ANXA3为该疾病潜在的致病基因,突变可导致其蛋白质高级结构的改变,可能与该疾病发生有关。结论:本研究为从分子水平上了解该家族遗传性疾病的发生提供了一定的理论参考。
OBJECTIVE: To find a group of special cases clinically in a family of 4 generations were found in patients with the same neuromuscular disease, the symptoms manifested as upper extremity elbow with varying degrees of extension is limited, the lower extremity ankle-like horseshoe-like Deformity, high bow deformity of the foot, no significant inversion of adduction phenomenon. In this study, it is planned to investigate the pathogenic genes and their molecular mechanisms of pathogenesis by genome-wide sequencing. Methods: Whole-genome sequencing was performed on blood samples of children, children with similar symptoms and healthy mothers by high-throughput sequencing. Bioinformatics analysis was used to screen for disease-related gene mutations, and further blood samples were collected from other affected and healthy members of this family for validation using PCR techniques. Results: Bioinformatics analysis revealed a series of mutations including ANXA3 gene mutation [chr4, c.C820T (p.R274 *)], ATP6V1E2 gene mutation [chr2, c.G136A (p.V46M)] and HIST1H3A gene mutation chr6, c.C205T (p.Q69 *)] and the like. Based on PCR results of more blood samples of family member, further confirms that ANXA3 is a potential causative gene of the disease. Mutation may result in the alteration of its higher protein structure, which may be related to the occurrence of the disease. Conclusion: This study provides a theoretical reference for understanding the occurrence of genetic familial diseases at the molecular level.