在高度混合的儿科人群中，类固醇抵抗型肾病综合征与独特的基因特征相关。
Steroid-Resistant Nephrotic Syndrome Is Associated With a Unique Genetic Profile in a Highly Admixed Pediatric Population.
作者信息
Watanabe Andreia, Miranda de Menezes Neves Precil Diego, Nunes Kelly, Lerario Antonio Marcondes, Watanabe Elieser Hitoshi, Ferreira Frederico Moraes, Avancini Costa Malheiros Denise Maria, de Moraes Narcizo Amanda, Guaragna Mara Sanches, de Almeida Araujo Stanley, Cruz Thais Medeiros, Fontes Jussara Soares, Santoro Belangero Vera Maria, Vaisbich Maria Helena, Hildebrandt Friedhelm, Sampson Matthew Gordon, Onuchic Luiz Fernando
机构信息
Department of Pediatrics, University of São Paulo School of Medicine, São Paulo, Brazil.
Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
出版信息
Kidney Int Rep. 2024 Sep 12;9(12):3501-3516. doi: 10.1016/j.ekir.2024.09.005. eCollection 2024 Dec.
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 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. high-risk genotypes were identified in 8% of families and causative Mendelian variants in 12%: = 3, = 3, = 2, = 2, = 1, and = 1. Two novel causative variants arose in the Native American background. The percentage of African genetic ancestry did not associate with the number of risk alleles. Forty-four percent of all patients progressed to KF. Mendelian forms and 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 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 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.
引言
在混合人群中，与激素抵抗性肾病综合征（SRNS）进展至肾衰竭（KF）相关的遗传和非遗传因素概况在很大程度上尚不清楚。
方法
总共101例原发性SRNS儿科患者接受了基因评估，采用62个肾病相关基因的基因检测板或全外显子测序来确定孟德尔病因和状态，以及遗传血统。使用美国医学遗传学与基因组学学会（ACMG）标准评估变异的致病性。
结果
54%的患者被诊断为局灶节段性肾小球硬化（FSGS），而13%的患者报告有家族性疾病。全球遗传血统为65%欧洲血统、22%非洲血统、10.5%美洲原住民血统和2%东亚血统，96%的病例呈现前三种成分。在8%的家族中鉴定出高风险基因型，12%的家族中鉴定出致病性孟德尔变异：NPHS1 = 3，NPHS2 = 3，WT1 = 2，TRPC6 = 2，LAMB2 = 1，和PLCE1 = 1。在美洲原住民背景中出现了两个新的致病性变异。非洲遗传血统的百分比与风险等位基因的数量无关。所有患者中有44%进展至KF。孟德尔形式和高风险基因型与更快进展至KF相关。Cox回归分析显示，较高的非欧洲遗传血统、自我申报的非白人种族、发病年龄<1岁或≥9岁，以及非微小病变性肾病（MCD）组织学与KF风险较高相关，与基因检测结果无关。
结论
在这个高度混合的人群中，孟德尔变异和高风险基因型构成了与儿科SRNS相关的独特致病基因概况，约占家族的20%。这种血统模式与非洲遗传血统比例低的儿童中高风险基因型的鉴定一致。自我申报的种族、发病年龄和组织学与KF风险独立相关。
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