Projects

Project Description

Monogenic kidney diseases with autosomal recessive inheritance represent a major cause of early-onset CKD (1). However, the burden of these diseases is unknown in our country. Carrier frequencies of recessive diseases can vary drastically among different populations (2). Most of these recessively inherited kidney diseases have moderate to severe phenotype leading to significant morbidity and mortality if not diagnosed early. Some of these monogenic kidney diseases have disease modifying therapy (eg Cystinosis, primary hyperoxaluria) or have extra renal manifestations that are often silent or subtle (eg Nephronophthisis). Hence carrier screening as well as early diagnosis through newborn screening are important considerations for prevention as well limiting morbidity and mortality through early interventions. It is important that recessive gene panels selected for newborn screening of monogenic kidney diseases and carrier screening be based on population-specific carrier frequencies in our country (3). Massively sequencing based testing is being increasingly used in the diagnosis of CKD in children in India, but the major challenge has been lower than expected diagnostic yield when compared to other population (4). The current variant classification methods overly depend on allele frequency from Western or European databases, which leads to under classification or ambiguity of variants in Indian patients (5,6). Knowing the population allele frequency data from diverse ethnic background in Indian population may help to distinguish between true disease-causing mutations and the remaining variants. Also, absence of functional data due to lack of appropriate model system recapitulating phenotype of the human tubular disorders such as distal renal acidosis tubular is another unmet need. Our collaborating team at NCBS has developed and validated a Drosophila nephrocyte model system for rare kidney disorders, such as Lowe syndrome. This model enables multiscale evaluation of renal function and is capable of recapitulating aspects of human renal tubular physiology. We now aim to utilize this model for the functional assessment of missense and loss-of-function variants in two of the most frequently mutated genes in Indian patients with tubulopathies: ATP6V0A4 and SLC4A1.

This proposal combines the national genomic resources, prior research findings, and established model system capabilities to address an unmet need in translational nephrogenetics in India.