Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management
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DOI：
10.1016/j.kint.2016.10.013
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发表时间：
2017-04-01
影响因子：
19.6
通讯作者：
Saleem, Moin A.
中科院分区：
文献类型：
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作者：
Bierzynska, Agnieszka;McCarthy, Hugh J.;Saleem, Moin A.
儿童和年轻人的类固醇耐药肾病综合征（SRNS）有不同的病因，在选定的系列中，单基因疾病占2.9-30%。使用全外显子组测序，我们试图将全国SRNS儿童人群分为单基因型和非单基因型，并通过详细的表型分析进一步定义这些群体。通过国家英国肾脏登记处确定SRNS儿科患者。对187名患者进行了全外显子组测序，其中12%有阳性家族史，重点关注目前已知与肾病综合征相关的53个基因。遗传学发现与个别病例的疾病特征相关。在26.2%的患者中检测到致病变异。这通常发生在三个最常见的SRNS相关基因中：NPHS 1，NPHS 2和WT 1，但也发生在其他14个基因中。基因型并不总是与预期的表型相关，因为在孤立性肾脏疾病患者中检测到与特定综合征相关的OCRL、COL 4A 3和DGKE突变。原发性/假定性与继发性类固醇耐药相比的分析发现，原发性单基因疾病占30.8%，而继发性SRNS中无单基因疾病，这允许进一步的机制分层。遗传性SRNS进展更快，终末期肾功能衰竭，在该队列中没有记录的移植后疾病复发。未发现基因突变的原发性类固醇耐药患者复发风险为47.8%。在这个无偏倚的儿科人群中，全外显子组测序允许筛选所有当前候选基因。因此，深度表型分型结合全外显子组测序是早期鉴定SRNS病因的有效工具，产生用于临床管理的循证算法。
Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and nonmonogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence -based algorithm for clinical management.