The Democratization of Genomic Inquiry Empowers Our Understanding of Nephrotic Syndrome.
The Democratization of Genomic Inquiry Empowers Our Understanding of Nephrotic Syndrome.
复制标题
基因组研究的民主化增强了我们对肾病综合征的理解。
DOI：
10.1097/tp.0000000000001897
复制
发表时间：
2017
期刊：
影响因子：
6.2
通讯作者：
Sampson,MatthewG
中科院分区：
文献类型：
--
作者：
Sampson,MatthewG
肾病综合征（NS）基因组基础研究的早期历史可以粗略地描述为少数具有技术和分析专业知识，财政资源和获得先天性或类固醇耐药（SR）NS的大激酶的研究人员发现了携带罕见编码变异的基因，这些变异足以破坏蛋白质导致疾病。“孟德尔NS基因”的发现是通过努力评估那些被诊断患有“孟德尔”NS的患者的表型相关性来实现的。这些早期的基因型-表型研究发现，孟德尔NS患者几乎总是有SRNS，但肾移植（KT）后NS没有复发。[1]然而，直到最近，这些发现对更广泛的基因和患者的普遍性还是未知的。幸运的是，下一代测序技术的快速发展和随之而来的成本下降导致了孟德尔NS诊断筛查的民主化。全世界的研究人员现在已经在成千上万的NS患者中测序了多达50个孟德尔NS基因。2-4这些研究进一步证实了孟德尔NS在家族性疾病儿童中的患病率较高，这些儿童来自近亲比例较高的国家，发病年龄较早，并且是SR（尽管越来越多的人认识到一些孟德尔NS患者实际上确实实现了蛋白尿的完全缓解5）。此外，对于进展为KT的患者，患有孟德尔形式NS的患者很少复发疾病。3总而言之，这些见解代表了我们为NS提供精确医学方法的努力的重大收获。然而，我们仍然有一个不完整的了解，在已知的孟德尔NS基因的致病性遗传变异的患病率及其相关的临床影响。部分知识差距可以通过对来自先前研究人群的更多患者的更多基因进行测序来解决。
The early history of inquiry into the genomic underpinnings of nephrotic syndrome (NS) can be roughly characterized as a small number of investigators with technological and analytical expertise, financial resources, and access to large kindreds with congenital or steroid-resistant (SR) NS discovering genes harboring rare coding variants sufficiently damaging to a protein to cause disease. The discovery of “Mendelian NS genes” was paralleled by efforts to assess the phenotypic correlates for those patients diagnosed with “Mendelian” NS. These early genotype-phenotype studies found that patients with Mendelian NS almost always had SRNS but did not have recurrence of NS after kidney transplant (KT). 1 However, until recently, the generalizability of these findings to a wider spectrum of genes and patients was unknown.Fortunately, the rapid advancements in next generation sequencing technologies and their concomitant decrease in cost has led to the democratization of diagnostic screening for Mendelian NS. Investigators worldwide have now sequenced up to 50 Mendelian NS genes in many thousands of patients with NS. 2-4 These studies have reinforced that the prevalence of Mendelian NS is higher in children with familial disease, those from countries with higher rates of consanguinity, who had an earlier age of onset, and who are SR (although there is increasing recognition that some patients with Mendelian NS in fact do achieve complete remission of proteinuria5). Also, for patients who progressed to KT, those with a Mendelian form of NS rarely had recurrent disease. 3 Altogether, these insights represent major gains toward our efforts provide a precision medicine approach to NS. Yet, we still have an incomplete understanding of the prevalence of pathogenic genetic variation in known Mendelian NS genes and their associated clinical impact. Part of this knowledge gap can be addressed by sequencing more genes in more patients from previously studied populations.