Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome
Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome
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DOI：
10.2215/cjn.04120417
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发表时间：
2018-01-06
影响因子：
9.8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Warejko, Jillian K.;Tan, Weizhen;Hildebrandt, Friedhelm
背景与目的激素耐药型肾病综合征（NS）绝大多数进展为终末期肾病（ESRD）。目前已发现30多个单基因可引起激素耐药型肾病综合征。我们以前在30%的类固醇耐药肾病综合征患者中使用靶向测序检测到致病突变。与全外显子组测序相比，面板测序具有许多局限性。我们采用全外显子组测序检测单基因类固醇耐药肾病综合征的原因在一个国际队列的300 family.Design，设置，参与者，和measurements从1998年4月至2016年6月，从300个家庭招募了335名类固醇耐药肾病综合征患者。发病年龄限制为25岁。外显子组数据进行了评估33个已知的单基因类固醇耐药肾病综合征genes.Results在74的300个家庭（25%），我们确定了一个致病突变的20个基因之一，已知引起类固醇耐药肾病综合征。在11个家庭（3.7%），我们检测到一个基因突变，导致类固醇耐药肾病综合征的表型。这与我们先前发表的使用面板方法鉴定突变一致。我们在38%的血缘家族和13%的非血缘家族以及48%的先天性肾病综合征患儿中检测到一种已知的类固醇耐药肾病综合征基因的致病突变。在33个激素耐药肾病综合征基因中的20个基因中共检测到68个不同的突变。这些突变中有15个是新的。NPHS1、PLCE 1、NPHS2和SMARCAL 1是我们检测到突变的最常见基因。在另外28%的家庭，我们检测到突变的一个或多个候选基因类固醇耐药nephropathicsyndrome.Conclusions全外显子组测序是一个敏感的方法，对类固醇耐药肾病综合征的单基因原因的诊断。激素耐药型肾病综合征的分子遗传学诊断可能对激素耐药型肾病综合征的治疗和肾移植管理具有重要意义。
Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to,25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were themost common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.