Gene–disease relationships for glomerular phenotypes: expert recommendations from ClinGen

Abstract

Glomerular diseases are complex conditions, many of which have a genetic basis. However, although some genetic variants can affect glomerular and thereby kidney function, not all identified variants are pathogenic. The process of evaluating genetic and experimental evidence to determine the validity of gene–disease relationships is known as gene curation, and it is critical for the identification of genes that should be examined in diagnostic tests and used to guide clinical management. Gene curation is a key role of the Clinical Genome Resource (ClinGen) and aims to ensure that the evidence underlying asserted gene–disease relationships across a range of diseases is sufficiently robust through comprehensive review of evidence and standardized evaluation by genetic and disease area-specific experts. The ClinGen Glomerulopathy Gene Curation Expert Panel has evaluated 57 gene–disease relationships from 56 genes that have been putatively linked to glomerular phenotypes. This evaluation identified 34 genes that reached a definitive level of evidence for gene–disease clinical validity. Ten genes had moderate supporting evidence and 11 had limited supporting evidence. A further two genes had insufficient evidence for any clinically valid relationship to disease. This curation establishes a comprehensive framework for the ongoing assessment of gene–disease relationships and provides a valuable reference for diagnostic genetic testing panels that target glomerular disease.