Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome

Abstract

Background The aim of this study was to elucidate whether genetic screening test results of pediatric steroid-resistant nephrotic syndrome (SRNS) patients vary with ethnicity. Methods Using high-throughput DNA sequencing, 28 nephrotic syndrome-related genes were analyzed in 110 children affected with SRNS and 10 children with isolated proteinuria enrolled by 5 centers in China (67 males, 53 females). Their age at disease onset was 1 day to 208 months (median, 48.8 months). Patients were excluded if their age of onset of disease was beyond 18 years or if they were diagnosed as Alport’s syndrome. Results A genetic etiology was identified in 28.3% of our cohort and the likelihood of establishing a genetic diagnosis decreased as the age of onset of nephrotic syndrome increased. The most common mutated genes were ADCK4 (6.67%), NPHS1 (5.83%), WT1 (5.83%), and NPHS2 (3.33%), and the difference in the frequencies of ADCK4 and NPHS2 mutations between this study and a study on monogenic causes of SRNS in the largest international cohort of 1,783 different families was significant. A case with congenital nephrotic syndrome was attributed to a homozygous missense mutation in ADCK4, and a de novo missense mutation in TRPC6 was detected in a case with infantile nephrotic syndrome. Conclusions Our results showed that, in the first and the largest multicenter cohort of Chinese pediatric SRNS reported to date, ADCK4 is the most common causative gene, whereas there is a low prevalence of NPHS2 mutations. Our data indicated that the genetic testing results for pediatric SRNS patients vary with different ethnicities, and this information will help to improve management of the disease in clinical practice.

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

“…In contrast to previous studies [9], in a large multicentre cohort of Chinese paediatric patients with SRNS, ADCK4 was found to be the most commonly mutated causative gene, responsible for SRNS presenting as early as the congenital period, but most frequently during childhood [10].…”

“…Indeed, mutations have been identified in 75-100% of cases of CNS [8,10,65,66]. Causative mutations appear to largely occur in one of five genes (NPHS1, NPHS2, WT1, LAMB2 and PLCE1).…”

“…NPHS1, encoding nephrin, is the main gene implicated in CNS, and mutation is responsible for the autosomal recessive Finnish type (CNF), which typically has a severe phenotype with massive proteinuria and rapid progression to ESRD [11]. However, the NPHS1 mutation detection rate remains high amongst non-Finnish cases of CNS [8,10,65]. Mutations in the NPHS2 gene, encoding podocin, are also responsible for a significant number of CNS cases, and the phenotype varies from the severe CNF presentation to milder disease with onset of proteinuria occurring later than in those with NPHS1 mutations [4,66,67].…”

“…This is especially true for patients of Chinese, Japanese and Korean origin, as there appears to be an increased frequency of the ADCK4 mutation in these populations [10,70]. Additionally, given that the APOL1 genotype represents a vulnerable population who present with more advanced disease [108], defining a patient's APOL1 genotype has important clinical implications, and mutational screening of this gene should be included in the gene panel, especially for patients of African descent.…”

The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome

“…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].…”