Genetics of Childhood Nephrotic Syndrome

Studies of hereditary steroid resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) have generated data to improve our understanding of the pathogenesis of nephrotic syndrome (NS); however, little progress has been made in identifying genetic factors associated with the predominant form of NS, childhood onset steroid sensitive nephrotic syndrome (SSNS). SSNS is responsible for more than 80% of cases seen by Pediatric Nephrologists, yet the biologic basis for disparity in incidence and severity of SSNS between different ethnicities is unknown, neither is the biologic basis for variable therapy response. As a first step towards understanding the more common SSNS, in the last ten years we have created a robust biorepository for childhood onset NS. We now have phenotype and biosamples from over 1000 children with NS. We recently used a novel study design to identify, for the first time, an unbiased exome wide risk locus for childhood SSNS in a subset of our cohort. The locus provided an unbiased genetic evidence that adaptive immunity is important in the pathogenesis of NS. We have continued to build network to study this disease and we have extended our reach to multiple Investigators in the US, UK, Japan, sub-Saharan African countries, South Asian countries, and the Middle East. These collaborations have resulted in the identification of other genetic risk factors for childhood onset nephrotic syndrome. The body of work from these International collaborations have reinforced our initial findings that childhood nephrotic syndrome is largely due to perturbation of adaptive immunity, and these findings has now set the stage for discovery of novel and specific therapeutics for nephrotic syndrome.