Comprehensive genetic diagnosis of Japanese patients with severe proteinuria

Abstract

Numerous disease-causing gene mutations have been identified in proteinuric diseases, such as nephrotic syndrome and glomerulosclerosis. this report describes the results of comprehensive genetic diagnosis of Japanese patients with severe proteinuria. in addition, the report describes the clinical characteristics of patients with monogenic disease-causing mutations. We conducted comprehensive gene screening of patients who had either congenital nephrotic syndrome, infantile nephrotic syndrome, steroid-resistant nephrotic syndrome, or focal segmental glomerular sclerosis. Using targeted next-generation sequencing, 60 podocyte-related genes were screened in 230 unrelated patients with proteinuria. A retrospective review of clinical data was conducted for these patients. We detected monogenic disease-causing mutations in 30% (69 of 230) of patients among 19 of the screened genes. common genes with disease-causing mutations were WT1 (25%), NPHS1 (12%), INF2 (12%), TRPC6 (10%), and LAMB2 (9%). With various immunosuppressive or renoprotective therapies, remission of proteinuria in patients with unknown causative mutations was observed in 26% of patients, whereas only 5% of patients with monogenic disease-causing mutations exhibited complete remission. We assessed the genetic backgrounds of Japanese patients with severe proteinuria. the proportion of patients with gene defects was similar to that of other reports, but the disease-causing gene mutation frequency was considerably different.

Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis

“…Another interesting finding in this study is the higher prevalence of mutations in COQ6, COQ8B and NUP107, which was consistent with our previous studies [26][27][28]. An increased prevalence of COQ8B mutations was also found in a Chinese study [5], while an increased prevalence of NUP107 mutations was found in a Japanese study [6].…”

“…This study showed a higher mutation detection rate in patients who presented with proteinuria than in patients who presented with NS (57.0% versus 34.5%, p < 0.001). Similarly, in a Japanese study [6], the absence of edema was one of the risk factors for genetic mutations in pediatric patients with severe proteinuria. In this study, the mutation detection rate was higher in patients without steroid treatment than in patients with initial steroid non-responsiveness (63.9% versus 39.7%, p < 0.001).…”

“…An international study [23] using WES showed a low prevalence of NPHS2 and WT1 mutations because many enrolled individuals were screened for mutations in WT1 and NPHS2 before performing WES, and those who screened positive were excluded. Moreover, a Japanese study [6] showed that none of the 230 unrelated patients with proteinuria had NPHS2 mutations, and a Chinese study [5] showed that NPHS2 mutations were detected in 4 (3.3%) of 120 children with SRNS or isolated proteinuria, which accounted for 11.8% of 33 patients with disease-causing mutations. The lower prevalence of NPHS2 mutations in Asian countries, including Korea, may be due to the absence of common mutations, i.e., a founder effect [4,24,25].…”

“…Recent advances in next-generation sequencing (NGS) techniques make genetic diagnosis more feasible in SRNS patients. Recent large cohort studies [3][4][5][6] revealed genetic mutations in approximately 30% of pediatric patients with SRNS/FSGS. Benefits of genetic diagnosis in patients with SRNS include providing definitive diagnosis and valuable information for decisions on treatment policy and prediction of prognosis.…”

Genetic tests in children with steroid-resistant nephrotic syndrome

“…However, recent advances in next-generation sequencing (NGS) have provided a revolutionary new approach for genetic diagnosis in terms of cost and effectiveness by allowing a panel of candidate genes or whole genes to be sequenced simultaneously. Mutations have been detected in approximately 30% of childhood-onset SRNS cases, according to large-cohort studies using NGS (Table 1) [2][3][4][5][6][7]. Thus, clinicians must select the best diagnostic tool for patients with a suspected genetic disorder.…”