Ms HANNAH FABROS1,2, DR. STEPHEN ALEXANDER1,2, DR. HUGH MCCARTHY1,2
1The Children’s Hospital at Westmead, Sydney, Australia, 2The University of Sydney, Sydney, Australia
Background: 20% of Childhood Nephrotic Syndrome is resistant to steroid therapy (SRNS) and of these, 50% will develop progressive chronic kidney disease leading to end stage within 5 years. In 20% of SRNS patients, monogenic causes (dominant and recessive) have been identified primarily in genes expressed in the podocyte. In the remaining cohort, aetiology is presumed immune-mediated with putative circulating factor(s) causing nephrotic syndrome. This theory is exemplified by risk of recurrence in gene-negative disease of >40%. Suggested circulating factors/pathways include both Th2 and ILC2 (Type 2 Innate Lymphoid Cells) pathways due to the association with allergy and Interleukin-4 / Interleukin-13.
Method: We performed Whole Genome Sequencing (WGS) on three unrelated children with post-transplant recurrent SRNS where diagnostic gene panels had been uninformative. We re-interrogated the WGS using the 83 genes in the PanelApp knowledge base associated with proteinuria and then also using 17 genes associated with ILCs (Innate Lymphoid Cells).
Results: No disease-causing variants were identified in the genes associated with monogenic causes of nephrotic syndrome. 183 rare variants were identified in 4 genes associated with ILC function: ST6GALNAC3, CDON, ATP8A2, and SLC27A6. However, no exonic or splice site variants were shared between the three unrelated children.
Conclusions:
Aetiology of recurrent disease post-transplant in childhood SRNS remains poorly understood. Risk alleles or monogenic causes within the immune system could offer an explanation. This preliminary study did not reveal strong candidate variants within ILC genes but points to a new research focus that requires study.
Biography:
Bio to come