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. 2022 May 5;9(6):1662-1673.
doi: 10.1016/j.gendis.2022.03.023. eCollection 2022 Nov.

Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome

Jia Jiao  1 , Li Wang  2 , Fenfen Ni  3 , Mo Wang  1 , Shipin Feng  2 , Xiaojie Gao  3 , Han Chan  1 , Xueying Yang  1 , Hao Lee  1 , Huan Chi  1 , Xuelan Chen  1 , Daoqi Wu  1 , Gaofu Zhang  1 , Baohui Yang  1 , Anshuo Wang  1 , Qin Yang  1 , Junli Wan  1 , Sijie Yu  1 , Xiaoqin Li  1 , Mei Wang  1 , Xiaofeng Chen  1 , Xianying Mai  1 , Xiongzhong Ruan  4   5 , Haiping Yang  1 , Qiu Li  1
Affiliations

Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome

Jia Jiao et al. Genes Dis. .

Abstract

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.

Keywords: Clinical phenotypes; Genetic phenotypes; Multicenter cohort; Nephrotic syndrome; Pediatric; Whole-exome sequencing.

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Figures

Figure 1
Figure 1
Flowchart for the selection of 637 patients included in the study.
Figure 2
Figure 2
Proportion of individuals with causative mutations in presumed steroid resistant and idiopathic SRNS patients, divided by sex, age and pathology.
Fig. 3
Figure 3
The proportion of gene distribution in idiopathic SRNS.
Fig. 4
Figure 4
The distribution of causitive mutation genes in different age groups in idiopathic SRNS.
Fig. 5
Figure 5
Kidney survival in the genetic and genetic mutation negative group of patients.
See this image and copyright information in PMC

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