Abstract
Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice.Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants.Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (χ2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS.Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.
Highlights
Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults
Ninety-five individuals were enrolled who had no family history of steroid-resistant nephrotic syndrome (SRNS) or chronic kidney disease (CKD). These individuals were classified as having sporadic disease
In a large international study of patients with SRNS that showed a 30% prevalence of monogenic Nephrotic syndrome (NS), fewer than 20% of families were from the United States, and many were from regions with a high degree of consanguinity [16]
Summary
Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Nephrotic syndrome (NS) is a clinical syndrome characterized by massive proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia. It may be complicated by venous thromboembolism, cardiovascular disease, and increased risk of infections due to loss of immunoglobulins [1, 2]. With an annual incidence of 2–7 per 100,000 and a prevalence rate of 16 per 100,000, NS is the most common glomerular disease in children and adults [2,3,4]. The majority of patients with steroid-resistant nephrotic syndrome (SRNS) will progress to end-stage kidney disease (ESKD) within 5–10 years of diagnosis [7, 8]. SRNS accounts for >10% of all cases of children with ESKD and is the most prevalent diagnosis among children receiving maintenance dialysis [1, 9, 10]
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