Nephrotic syndrome (NS) is a rare kidney disease resulting from malfunction of the primary ultra-filtration unit in the kidney, the renal glomerulus, leading to excessive leak of protein into urine. NS has an annual incidence of 2 and 7 per 100,000 children and adults, and a prevalence of 1 to 15 per 100,000 depending on the ethnicity; NS is more common in African and South Asian populations. However, despite its rare disease status, it remains one of the most common kidney diseases to affect children and adults. It has a devastating impact on the health of affected individuals, with around 20% of cases developing end stage kidney failure and 60% of the severe group experiencing disease recurrence post kidney transplant. Mendelian inheritance appears only to explain around 30% of cases. Inheritance may be autosomal recessive or dominant with variable penetrance and more recently Xlinked has also been described. To date, causal genetic variants have been identified in 67 genes in NS patients. However, the molecular genetic mechanisms underlying the remaining 70% remain poorly understood and are likely to fall into a complex genetic category. The aim of this study was to identify causal genetic variation of NS, focusing on the 70% of cases currently unexplained by single mutations in previously established nephrotic syndrome genes. A cohort of 485 deeply phenotyped patients was available for analysis; all have undergone whole exome sequencing or whole genome sequencing. Data was analysed by applying computational approaches including linkage and association analyses. Based on this, a link with HLA was identified, confirming that despite a lack of typical inflammatory markers, NS in both children and adults falls into the category of an autoimmune disease.