Genetic Analysis in Children with End Stage Renal Disease: Insight from the Rambam Nephrogenetic Project

Background: The prevalence of monogenic disorders among children with chronic kidney disease (CKD) is approximately ~25%, with a higher estimated rate in pediatric end stage renal disease (ESRD). Our center serves consanguineous communities from northern Israel and the Palestinian territories, encountering a high rate of hereditary disorders. Advancement in sequencing technology has improved the detection rate of hereditary kidney diseases, thereby enabling timely genetic diagnosis, improved prenatal counseling and treatment optimization, among others.

Aim: Explore the molecular basis of suspected monogenic kidney disorders, in children with ESRD.

Methods: Children with ESRD of unknown or suspected genetic etiology were analyzed, using exome sequencing (ES), or targeted gene sequencing.

Results: During a 4-year period, we performed genetic analysis in 43 patients from 40 families with ESRD due to unknown or suspected hereditary etiology. We used ES and targeted gene sequencing in 32 (74%) and in 11 (26%) patients, respectively. Disease causing variants were identified in 26 patients (60%). In more than half of the cases, molecular diagnosis had significant impact on clinical decision making, due to change of suspected diagnosis, modification of treatment, exclusion of potential living-related donor, and informative prenatal counseling. Five novel disease-causing candidate genes were identified, awaiting further functional analysis.

Conclusions: Genetic analysis in children with ESRD of unknown or suspected hereditary etiology provides a high detection rate of disease-causing variants, and profoundly improves patient management. We therefore suggest that genetic analysis should become standard of care for pediatric CKD and ESRD of inconclusive etiology.