背景:基因组关联研究表明,基因-基因相互作用或上位性在确定病因中起着至关重要的作用,预后,和许多复杂疾病的治疗反应超出了它们的主要影响。骨骼发育不良是一组异质性的先天性骨和软骨疾病,具有遗传和先天相互作用的病因。目前骨骼发育不良的分类区分了42组的461种疾病,所有骨骼发育不良的发生率超过每5000个新生儿中的1个。目的是介绍具有四种变体的患者的情况,这些变体在骨骼发育不良中产生了生源相互作用。
方法:一名1岁男性患者被诊断为骨骼发育不良,根据产前超声显示微蜂窝和肾盂扩张。产后体格检查显示身体比例不均,其他器官和系统受累。
方法:对358个与骨骼发育不良相关的候选基因进行测序研究和缺失/重复分析。GeneMANIA接口用于评估彼此相关的基因的表达网络,以进行世代相互作用。
结果:在SLC26A中获得了两种具有致病性意义的杂合变体,CLCN7中的一个杂合子致病变体和CEP120中的另一个杂合子致病变体。GeneMANIA接口显示77.64%的物理相互作用,8.01%共表达,5.37%预测,3.63%共同本地化,2.87%的遗传相互作用,1.88%的行动路线,和0.60%共享的蛋白质结构域。
结论:这些结果表明,这些基因之间的相互作用会影响无机阴离子交换剂的活性,导致胶原纤维的解体,早期矿化,和减少纤维连接蛋白在骨细胞外基质中的组装。识别基因-基因相互作用是理解适当细胞功能并因此理解许多复杂人类疾病的病理生理学的基本步骤。改善诊断,以及新的个性化疗法的可能性。
BACKGROUND: Genome association studies have shown that gene-gene interactions or epistasis play a crucial role in identifying the etiology, prognosis, and treatment response of many complex diseases beyond their main effects. Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic and gen-gen interaction etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups, and the incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The objective is to present the
case of a patient with four variants that generates gen-gen interactions in the skeletal dysplasia.
METHODS: A 1-year-old male patient was diagnosed with skeletal dysplasia based on prenatal ultrasound showing micromelia and pyelocalyceal dilation. Postnatal physical examination revealed body disproportion and involvement of other organs and systems.
METHODS: A sequencing study and deletions/duplications analysis were performed for 358 candidate genes associated with skeletal dysplasia. The GeneMANIA interface was used to evaluate the expression network of genes associated with each other for the gen-gen interaction.
RESULTS: Four pathogenic variants were obtained two heterozygous variants with pathogenic significance in SLC26A, one heterozygous pathogenic variant in CLCN7 and another heterozygous pathogenic variant in CEP120. The GeneMANIA interface reveals 77.64% physical interactions, 8.01% co-expression, 5.37% prediction, 3.63% co-localization, 2.87% genetic interactions, 1.88% route of action, and 0.60% shared protein domains.
CONCLUSIONS: These results suggest that the interaction between these genes affects the activity of the inorganic anion exchanger, leading to disorganization of collagen fibers, early mineralization, and decreased assembly of fibronectin in the bone extracellular matrix. Identifying gene-gene interactions is a fundamental step in understanding proper cell function and thus understanding the pathophysiology of many complex human diseases, improving diagnosis, and the possibilities of new personalized therapies.