Steroid-Resistant Nephrotic Syndrome Is Associated With a Unique Genetic Profile in a Highly Admixed Pediatric Population

IF 5.7 2区 医学 Q1 UROLOGY & NEPHROLOGY
Andreia Watanabe , Precil Diego Miranda de Menezes Neves , Kelly Nunes , Antonio Marcondes Lerario , Elieser Hitoshi Watanabe , Frederico Moraes Ferreira , Denise Maria Avancini Costa Malheiros , Amanda de Moraes Narcizo , Mara Sanches Guaragna , Stanley de Almeida Araujo , Thais Medeiros Cruz , Jussara Soares Fontes , Vera Maria Santoro Belangero , Maria Helena Vaisbich , Friedhelm Hildebrandt , Matthew Gordon Sampson , Luiz Fernando Onuchic
{"title":"Steroid-Resistant Nephrotic Syndrome Is Associated With a Unique Genetic Profile in a Highly Admixed Pediatric Population","authors":"Andreia Watanabe ,&nbsp;Precil Diego Miranda de Menezes Neves ,&nbsp;Kelly Nunes ,&nbsp;Antonio Marcondes Lerario ,&nbsp;Elieser Hitoshi Watanabe ,&nbsp;Frederico Moraes Ferreira ,&nbsp;Denise Maria Avancini Costa Malheiros ,&nbsp;Amanda de Moraes Narcizo ,&nbsp;Mara Sanches Guaragna ,&nbsp;Stanley de Almeida Araujo ,&nbsp;Thais Medeiros Cruz ,&nbsp;Jussara Soares Fontes ,&nbsp;Vera Maria Santoro Belangero ,&nbsp;Maria Helena Vaisbich ,&nbsp;Friedhelm Hildebrandt ,&nbsp;Matthew Gordon Sampson ,&nbsp;Luiz Fernando Onuchic","doi":"10.1016/j.ekir.2024.09.005","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><div>The profile of genetic and nongenetic factors associated with progression to kidney failure (KF) in steroid-resistant nephrotic syndrome (SRNS) is largely unknown in admixed populations.</div></div><div><h3>Methods</h3><div>A total of 101 pediatric patients with primary SRNS were genetically assessed targeting Mendelian causes and <em>APOL1</em> status with a 62-NS-gene panel or whole exome sequencing, as well as genetic ancestry. Variant pathogenicity was evaluated using the American College Medical of Genetics and Genomics (ACMG) criteria.</div></div><div><h3>Results</h3><div>Focal segmental glomerulosclerosis (FSGS) was diagnosed in 54% of patients whereas familial disease was reported by 13%. The global genetic ancestry was 65% European, 22% African, 10.5% Native American, and 2% East-Asian, while 96% of cases presented with the first 3 components. <em>APOL1</em> high-risk genotypes were identified in 8% of families and causative Mendelian variants in 12%: <em>NPHS1</em> = 3, <em>NPHS2</em> = 3, <em>PLCE1</em> = 2, <em>WT1</em> = 2, <em>COQ2</em> = 1, and <em>CUBN</em> = 1. Two novel causative variants arose in the Native American background. The percentage of African genetic ancestry did not associate with the number of <em>APOL1</em> risk alleles. Forty-four percent of all patients progressed to KF. Mendelian forms and <em>APOL1</em> high-risk genotypes were associated with faster progression to KF. Cox regression analyses revealed that higher non-European genetic ancestry, self-declared non-White ethnicity, age of onset &lt;1 year or ≥9 years, and non-minimal change disease (MCD) histology associated with higher risk of KF, independently of genetic findings.</div></div><div><h3>Conclusion</h3><div>Mendelian variants and <em>APOL1</em> high-risk genotype compose a unique causative genetic profile associated with pediatric SRNS in this highly admixed population, accounting for approximately 20% of families. This ancestry pattern is consistent with the identification of <em>APOL1</em> high-risk genotypes in children with low proportion of African genetic ancestry. Self-declared ethnicity, age of manifestation and histology were independently associated with the risk of KF.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"9 12","pages":"Pages 3501-3516"},"PeriodicalIF":5.7000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652071/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney International Reports","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2468024924019235","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction

The profile of genetic and nongenetic factors associated with progression to kidney failure (KF) in steroid-resistant nephrotic syndrome (SRNS) is largely unknown in admixed populations.

Methods

A total of 101 pediatric patients with primary SRNS were genetically assessed targeting Mendelian causes and APOL1 status with a 62-NS-gene panel or whole exome sequencing, as well as genetic ancestry. Variant pathogenicity was evaluated using the American College Medical of Genetics and Genomics (ACMG) criteria.

Results

Focal segmental glomerulosclerosis (FSGS) was diagnosed in 54% of patients whereas familial disease was reported by 13%. The global genetic ancestry was 65% European, 22% African, 10.5% Native American, and 2% East-Asian, while 96% of cases presented with the first 3 components. APOL1 high-risk genotypes were identified in 8% of families and causative Mendelian variants in 12%: NPHS1 = 3, NPHS2 = 3, PLCE1 = 2, WT1 = 2, COQ2 = 1, and CUBN = 1. Two novel causative variants arose in the Native American background. The percentage of African genetic ancestry did not associate with the number of APOL1 risk alleles. Forty-four percent of all patients progressed to KF. Mendelian forms and APOL1 high-risk genotypes were associated with faster progression to KF. Cox regression analyses revealed that higher non-European genetic ancestry, self-declared non-White ethnicity, age of onset <1 year or ≥9 years, and non-minimal change disease (MCD) histology associated with higher risk of KF, independently of genetic findings.

Conclusion

Mendelian variants and APOL1 high-risk genotype compose a unique causative genetic profile associated with pediatric SRNS in this highly admixed population, accounting for approximately 20% of families. This ancestry pattern is consistent with the identification of APOL1 high-risk genotypes in children with low proportion of African genetic ancestry. Self-declared ethnicity, age of manifestation and histology were independently associated with the risk of KF.

Abstract Image

在高度混合的儿科人群中,类固醇抵抗性肾病综合征与独特的遗传谱有关。
在混合人群中,与类固醇抵抗性肾病综合征(SRNS)进展为肾衰竭(KF)相关的遗传和非遗传因素的概况在很大程度上是未知的。方法:通过62- ns基因面板或全外显子组测序以及遗传祖先,对101例原发性SRNS患儿进行孟德尔病因和APOL1状态的遗传评估。变异致病性采用美国医学院遗传与基因组学(ACMG)标准进行评估。结果:局灶节段性肾小球硬化(FSGS)在54%的患者中被诊断出来,而家族性疾病报告的比例为13%。全球遗传祖先65%为欧洲人,22%为非洲人,10.5%为美洲原住民,2%为东亚人,而96%的病例具有前3种成分。8%的APOL1高危基因型和12%的孟德尔致病基因型分别为:NPHS1 = 3、NPHS2 = 3、PLCE1 = 2、WT1 = 2、COQ2 = 1和CUBN = 1。在印第安人的背景下出现了两种新的致病变体。非洲遗传血统的百分比与APOL1风险等位基因的数量无关。44%的患者进展为KF。孟德尔型和APOL1高危基因型与KF的快速进展相关。Cox回归分析显示,较高的非欧洲遗传血统、自我声明的非白人种族、发病年龄。结论:孟德尔变异和APOL1高危基因型构成了与这一高度混合人群中儿童SRNS相关的独特致病遗传谱,约占20%的家庭。这种祖先模式与非洲遗传血统比例低的儿童的APOL1高危基因型的鉴定一致。自我声明的种族、表现年龄和组织学与KF的风险独立相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Kidney International Reports
Kidney International Reports Medicine-Nephrology
CiteScore
7.70
自引率
3.30%
发文量
1578
审稿时长
8 weeks
期刊介绍: Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信