Kidney Week 2025 Early Program - Genetics in Clinical Nephrology-A Guide to Gene-Disease Relationships in Nephrology

A Guide to Gene-Disease Relationships in Nephrology

Pdf Summary

This review explains why rigorously defining gene–disease relationships is essential for accurate genomic diagnosis and precision care in nephrology. Next-generation sequencing (exome/genome sequencing) has rapidly expanded the number of implicated monogenic kidney disease genes to over 600, with monogenic causes accounting for ~50% of paediatric and ~10% of adult kidney disease, and up to 20% of transplant candidates. Genomic diagnoses can change management by guiding prognosis, avoiding invasive biopsies, informing transplant and reproductive decisions, enabling family cascade testing, and increasingly determining access to targeted therapies (e.g., ADPKD, complement-mediated disease, APOL1-associated kidney disease).<br /><br />The authors emphasize that variant interpretation (often using ACMG/AMP guidelines) depends fundamentally on whether the underlying gene–disease relationship is valid. However, gene panel content and laboratory practices vary widely, partly because gene–disease curation has lagged behind variant interpretation. They outline principles for assessing gene–disease validity using genetic evidence (case-level segregation, de novo occurrence, case-control data, inheritance consistency) and experimental evidence (expression, pathway relevance, model systems, rescue), and highlight that historical assertions can be overturned by population frequency data and improved standards (e.g., disputed SIX5–branchio-oto-renal association).<br /><br />The review surveys major curation resources (OMIM, Orphanet, ClinGen, PanelApp) and explains how differing terminology and evidence thresholds create discrepancies. Harmonization efforts are advancing via the Gene Curation Coalition (GenCC), which promotes standardized terms for validity, inheritance/allelic requirement, and mechanism, and supports discordance resolution.<br /><br />ClinGen’s Kidney Disease Clinical Domain Working Group is curating gene–disease relationships across major kidney disease categories using a semi-quantitative framework and expert review, alongside variant-focused expert panels (e.g., Alport, PKD). Finally, the authors argue kidney disease nomenclature should evolve with genetics, proposing a dyadic naming model (“core disease name – gene name”) supported by stable ontologies (e.g., MONDO) to improve clarity, computability, and patient care.

Keywords

gene–disease validity

monogenic kidney disease

next-generation sequencing

exome genome sequencing

ACMG AMP variant interpretation

gene panel curation

ClinGen Kidney Disease Working Group

Gene Curation Coalition GenCC

nephrology precision medicine

kidney disease nomenclature dyadic model