Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression
Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression
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DOI：
10.1681/asn.2013111155
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发表时间：
2015-01-01
影响因子：
13.6
通讯作者：
Romagnani, Paola
中科院分区：
文献类型：
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作者：
Giglio, Sabrina;Provenzano, Aldesia;Romagnani, Paola
在儿童中，散发性肾病综合征可能与遗传原因有关，但遗传改变在多大程度上与免疫抑制抵抗有关尚不清楚。在这项研究中，我们设计了一个自定义阵列，用于对19个靶基因进行下一代测序分析，这些基因被报道为肾病综合征的可能原因，在一个由31名受散发性类固醇耐药肾病综合征影响的儿童和38名表现出相似但类固醇敏感的临床表型的患者组成的队列中。有肾外症状、有家族病史或有血缘关系或先天性发病的患者被排除在外。我们确定了32.3%的类固醇耐药儿童的遗传原因，但38名类固醇敏感性疾病儿童中没有遗传原因。遗传变异也与类固醇耐药儿童对免疫抑制剂缺乏反应有关（0%的变异患者对免疫抑制剂有反应，57.9%的无变异患者对免疫抑制剂有反应），而临床特征、发病年龄和病理学结果在有和无变异的类固醇耐药患者中相似。这些结果表明，散发性肾病综合征患儿的异质性遗传改变与对类固醇和免疫抑制治疗的耐药性有关。因此，在这些患者中，使用这种阵列进行全面筛查可能有助于遗传咨询，并可能有助于以快速和具有成本效益的方式做出临床决策。
In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner.