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The expanding phenotypic spectra of kidney diseases: insights from genetic studies

Nature Reviews Nephrology volume 12, pages 472–483 (2016)Cite this article

Subjects

Key Points

  • Findings from next-generation sequencing (NGS) have led to a shift in phenotypic boundaries and reclassifications of some kidney diseases

  • NGS techniques are a valuable addition to the diagnostic toolbox in nephrology and findings from NGS can have important implications for therapeutic strategies and clinical outcomes

  • Interpretation of genetic variants and accurate prediction of the associated kidney phenotype can be challenging despite the increasing availability of bioinformatics tools and functional tests

  • Data sharing initiatives are imperative to establish clinically useful genotype–phenotype correlations and to maximize the benefit of genetic testing in routine nephrology practice

Abstract

Next-generation sequencing (NGS) has led to the identification of previously unrecognized phenotypes associated with classic kidney disease genes. In addition to improving diagnostics for genetically heterogeneous diseases and enabling a faster rate of gene discovery, NGS has enabled an expansion and redefinition of nephrogenetic disease categories. Findings from these studies raise the question of whether disease diagnoses should be made on clinical grounds, on genetic evidence or a combination thereof. Here, we discuss the major kidney disease-associated genes and gene categories for which NGS has expanded the phenotypic spectrum. For example, COL4A3–5 genes, which are classically associated with Alport syndrome, are now understood to also be involved in the aetiology of focal segmental glomerulosclerosis. DGKE, which is associated with nephrotic syndrome, is also mutated in patients with atypical haemolytic uraemic syndrome. We examine how a shared genetic background between diverse clinical phenotypes can provide insight into the function of genes and novel links with essential pathophysiological mechanisms. In addition, we consider genetic and epigenetic factors that contribute to the observed phenotypic heterogeneity of kidney diseases and discuss the challenges in the interpretation of genetic data. Finally, we discuss the implications of the expanding phenotypic spectra associated with kidney disease genes for clinical practice, genetic counselling and personalized care, and present our recommendations for the use of NGS-based tests in routine nephrology practice.

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Figure 1: The phenotypic spectrum of COL4A3–5 mutations.
Figure 2: Sources of phenotypic heterogeneity in nephrogenetic disease.
Figure 3: Implementation of next-generation sequencing (NGS) data in routine nephrology practice.

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Acknowledgements

The researchers receive funding from the Dutch Kidney Foundation under grant agreements CP11.18 Kouncil (N.V.A.M.K. and R.H.G.) and KSTP12 010 (A.M.v.E.), the European Community's Seventh Framework Programme (FP7/2009) under grant agreement 305608 EURenOmics (N.V.A.M.K., F.S. and K.Y.R.) and Fonds NutsOhra grant 1303–070 (A.M.v.E.).

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Authors and Affiliations

  1. Department of Genetics, Center for Molecular Medicine, KC04.084.2, University Medical Center Utrecht, PO BOX: 85090, Utrecht, 3508 AB, The Netherlands

    Marijn F. Stokman, Kirsten Y. Renkema, Nine V.A.M. Knoers & Albertien M. van Eerde

  2. Department of Nephrology and Hypertension, University Medical Center Utrecht, Regenerative Medicine Center-Hubrecht Institute, Uppsalalaan 8, Utrecht, 3584 CT, The Netherlands

    Rachel H. Giles

  3. Department of Paediatric Nephrology, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, BW69120, Germany

    Franz Schaefer

Authors
  1. Marijn F. Stokman
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  2. Kirsten Y. Renkema
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  3. Rachel H. Giles
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  4. Franz Schaefer
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  5. Nine V.A.M. Knoers
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  6. Albertien M. van Eerde
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Contributions

M.F.S. researched data for the article and wrote the article. All authors made substantial contributions to discussions of the article's content and reviewed/edited the manuscript before submission

Corresponding author

Correspondence to Nine V.A.M. Knoers.

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DATABASES

OMIM

256300

173900

603278

610805

256100

615008

235400

301050

141200

613820

613819

249000

213300

194070

194080

125850

616026

227810

161200

309000

300555

219000

601678

300009

263200

240300

311200

603965

ExAC database

Human Gene Mutation Database

Decipher

ClinVar

Glossary

Next-generation sequencing

A technique that enables the simultaneous investigation of mulitple genes and pathways in parallel. The term includes all forms of modern, high-throughput sequencing techniques, including gene panel sequencing, whole-exome sequencing and whole-genome sequencing.

Nephrogenetic diseases

Kidney diseases with a genetic aetiology, including hereditary kidney disorders for which the responsible genes have not yet been identified.

Pseudogenes

DNA sequences that are similar to genes but do not encode functional proteins.

Gene panel sequencing

Targeted sequencing of a set of genes that are associated with a specific phenotype.

Whole-exome sequencing

Targeted sequencing of all the protein-coding regions (1–2%) of the genome.

Whole-genome sequencing

Untargeted sequencing of the complete genome.

Causal

Variant(s) that are the cause of a specific phenotype.

Missense

A variant that results in a single amino-acid substitution.

Truncating

A variant that introduces a premature stop codon and results in a shortened protein.

Biallelic

Variant present on both alleles of a specific gene. Biallelic variants can be homozygous or compound heterozygous.

Probands

Patients who are the starting points of genetic studies in families.

Pathogenic

Variant that has an effect on protein function that is associated with a specific disease phenotype.

Hypomorphic

A mutation that results in reduced expression or reduced activity of a protein. The resulting disease phenotype is potentially milder than when mutations cause a complete loss of functional protein.

Phenotypic heterogeneity

When mutations in the same gene can give rise to two or more distinct clinical phenotypes.

Oligogenic inheritance

Inheritance model in which a phenotype is determined by the combination of a few genes.

Chromosome conformation capture

A technique used to study the in vivo organization and interactions of genomic elements.

Chromatin immunoprecipitation sequencing

A technique that combines chromatin immunoprecipitation with NGS to study the in vivo interaction between proteins (for example transcription factors) or epigenetic modifications (for example histone modifications) and the DNA.

Incidental findings

Findings that are unrelated to the condition for which the DNA test is performed, including alleles that confer disease-risk to the patient as well as carriership for recessive or X-linked disease.

Variants of unknown significance

Variants for which the association with disease risk is unknown.

Copy number variation

A type of structural variation that alters the diploid status of DNA (deletions and duplications).

Loss-of-function

Variant that results in a protein with reduced or no function.

Segregation analysis

Study of the association between a genetic variant and a specific phenotype in a family. It is used to establish the mode of inheritance and to investigate if a specific genetic variant could potentially be causal for the disease in a family.

Canonical

A canonical disease gene is a gene that is typically associated with a particular disease.

Replication stress

Occurs when replication fork progression is slow or problematic and can result in DNA damage and genomic instability.

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Stokman, M., Renkema, K., Giles, R. et al. The expanding phenotypic spectra of kidney diseases: insights from genetic studies. Nat Rev Nephrol 12, 472–483 (2016). https://doi.org/10.1038/nrneph.2016.87

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