Background

Steroid-sensitive nephrotic syndrome (SSNS) is the most common glomerulopathy in children, with an incidence of 1.15–16.9 per 100,000, varying by ancestry. Characterized by proteinuria, hypoalbuminemia, and oedema, about 80% of affected children respond to steroid therapy. Despite treatment, many experience relapses, and some develop steroid-dependent disease. While genetic causes of steroid-resistant nephrotic syndrome are known, the pathogenesis of SSNS remains unclear.

Aims

• Perform both long- and short-read sequencing (LaSR) on SSNS patients and controls.
• Develop an integrated analysis pipeline for complementary sequencing data.
• Compile a universal control set from open-access human genome sequences.
• Annotate and analyse candidate genomic variants

Methods

Previous GWAS studies have identified immune-related genetic loci associated with SSNS, suggesting an autoimmune component, but explain only a small fraction of heritability. This study will investigate larger genomic variants (>50 bp) using both sequencing methods. Short-read sequencing offers cost-effective detection of novel variants, but struggles with complex regions like HLA. Long-read sequencing excels at identifying structural variants and resolving repetitive regions. Combining both approaches maximises variant detection, improves cost-efficiency, and enhances applicability for rare diseases.

The study will focus on South Asian populations, collaborating with the University of Peradeniya in Sri Lanka to recruit SSNS patients and matched controls. The pilot phase will determine optimal sequencing depth to balance accuracy and cost, paving the way for broader clinical applications.