The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome
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EDITORIAL
The status quo and challenges of genetic diagnosis in children with steroid‑resistant nephrotic syndrome Yan‑Yan Jin1 · Bing‑Yu Feng1,2 · Jian‑Hua Mao1 Received: 27 February 2018 / Accepted: 28 March 2018 © Children’s Hospital, Zhejiang University School of Medicine 2018
Introduction Idiopathic nephrotic syndrome (INS) is one of the most common renal diseases in the pediatric population, which is characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia [1]. About 10–20% of affected children have steroid-resistant nephrotic syndrome (SRNS) and do not respond well to steroid therapy [2, 3]. Treatment of SRNS is very challenging due to its poor response to therapy and poor prognosis [4, 5]. Among the patients with SRNS, 20–40% will gradually progress to end-stage renal disease (ESRD) [6]. The etiology of SRNS can be genetic and non-genetic, such as infection- and immune-related factors [2]. The usage of genetic testing in the diagnosis of pediatric SRNS has significantly impacted its clinical management. Recent discoveries of genes encoding proteins crucial for the establishment and maintenance of glomerular filtration barrier have revealed the importance of glomerular epithelial cells (podocytes) in the pathogenesis of SRNS [7]. The most common histology of SRNS is focal segmental glomerular sclerosis (FSGS) [8]. About 11–50% of patients with FSGS are at risk of recurrence after kidney transplantation and eventually progress to terminal renal failure [8, 9], but the risk for recurrence is lower in FSGS patients with monogenic (single gene) forms of SRNS than those with nonhereditary forms [10]. One of the new factors that may predict response to therapy and renal outcomes is genetic variants of nephrotic syndrome [4]. Patients with genetic mutations are less likely
* Jian‑Hua Mao [email protected] 1
Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, #57 Zhugan Lane, Hangzhou 310003, China
Department of Paediatrics, The First People’s Hospital of Huzhou, Huzhou 313000, China
2
to respond to immunosuppressant therapy and more likely to develop ESRD [11].
Genes known to cause SRNS The first gene identified to cause SRNS was NPHS1 [12]; its pathogenic variants cause Finnish-type congenital nephrotic syndrome (CNS). Later on, a number of disease-causing genes have been discovered. To date, about 53 genes are known to cause SRNS and/or FSGS with all types of modes of inheritance [8]. According to its symptoms, SRNS can be isolated or syndromic, and the following 28 genes are known to cause isolated nephrotic syndrome [3, 8, 12, 13]: ADCK4, ARHGDIA, CD2AP, CFH, COQ2, COQ6, CUBN, DGKE, ITGA3, ITGB4, LAMB2, MEFV, MYO1E, NPHS1, NPHS2, PDSS2, PLCE1, PTPRO, SCARB2, SMARCAL1, TTC21B, ACTN4, ARHGAP24, INF2, LMX1B, PAX2, TRPC6, and WT1.
Detection rate of genetic cause in children with SRNS The variant detection rate of SRNS in children and young adults varies with different cohorts. Lipska et al. demonstrated that the overall mutation detection ra
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