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A guide to gene–disease relationships in nephrology

Nature Reviews Nephrology (2024)Cite this article

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Abstract

The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene–disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene–disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments.

Key points

  • Genomic sequencing technologies are transforming our understanding of genetic kidney disease.

  • Evidence-based frameworks, such as the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, are crucial to the appraisal of individual genetic variants and disease.

  • Curation of clinically relevant relationships between genes and specific phenotypes underpins accurate interpretation of genomic tests and, in turn, the ability to provide accurate and timely molecular diagnosis to patients, informing prognosis, recurrence risk counselling and, increasingly, access to precision treatments.

  • Several collaborative initiatives are undertaking gene–disease curation in genetic kidney disease within the international Gene Curation Coalition, including ClinGen, Genomics England PanelApp, Online Mendelian Inheritance in Man, Orphanet and PanelApp Australia.

  • The ClinGen Kidney Domain Working Group expert panels use the ClinGen semi-quantitative framework to systematically appraise gene–disease relationships in nephrology. Classifications are determined collaboratively between disease and curation experts on the basis of critical appraisal of human and experimental data and are publicly available.

  • As the molecular basis of genetic kidney diseases is elucidated, disease nomenclature will need to evolve; a two-tiered, dyadic naming model (core disease name–gene name), augmented with additional terms as applicable, can be applied consistently for most Mendelian kidney diseases.

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Fig. 1: Examples of genetic kidney disorders.
Fig. 2: From clinical assessment to diagnosis.
Fig. 3: Process of ClinGen gene curation.

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Acknowledgements

The authors acknowledge the support and contributions of the ClinGen Kidney Disease Clinical Domain Working Group and its associated Gene Curation and Variant Curation Expert Panels. A.J.M. is supported by a Queensland Health Advancing Clinical Research Fellowship. A.B.B. is supported by the ClinGen NIH grant U24 HG006834 (to Broad/Geisinger).

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Authors and Affiliations

  1. ClinGen, Boston, MA, USA

    Zornitza Stark, Alicia B. Byrne, Matthew G. Sampson, Rachel Lennon & Andrew J. Mallett

  2. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    Zornitza Stark

  3. Australian Genomics, Melbourne, Victoria, Australia

    Zornitza Stark

  4. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA

    Alicia B. Byrne

  5. Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA

    Matthew G. Sampson

  6. Department of Paediatrics, Harvard Medical School, Boston, MA, USA

    Matthew G. Sampson

  7. Wellcome Centre for Cell-Matrix Research, The University of Manchester, Manchester, UK

    Rachel Lennon

  8. Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK

    Rachel Lennon

  9. Townsville Hospital and Health Service, Townsville, Queensland, Australia

    Andrew J. Mallett

  10. College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia

    Andrew J. Mallett

  11. Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

    Andrew J. Mallett

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Glossary

Expressivity

Describes the degree to which different features of a disease manifest in affected individuals.

Penetrance

Describes the likelihood that an individual with a disease-causing gene variant will manifest clinical features of the disease.

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Stark, Z., Byrne, A.B., Sampson, M.G. et al. A guide to gene–disease relationships in nephrology. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00900-7

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