Genomic medicine for kidney disease

Key Points

  • Inherited aetiologies are responsible for 10% of adult end-stage renal disease and >70% of paediatric hephropathy; sequencing studies of large cohorts will shed further light on genetic contributions across different forms of kidney disease

  • In addition to ending the 'diagnostic odyssey', a genetic diagnosis can provide a deeper understanding of disease pathogenesis, inform prognosis, and guide clinical management

  • Genetic testing is currently recommended for patients with early-onset nephropathy and/or other clinical features consistent with an inherited form of disease as well as for evaluation of living kidney donors

  • Development of disease-specific guidelines and use of population genetic data will help to facilitate accurate clinical sequence interpretation; nevertheless, patient-level assessment results in the continued need for expert judgement

  • The broadening clinical use of genetic testing in nephrology has raised questions regarding the return of results, physician education, testing across different patient subpopulations and many other practical and ethical issues

  • Interdisciplinary research and dialogue will help to address unresolved challenges and inform the creation of best practice guidelines for genomic medicine in nephrology

Abstract

Technologies such as next-generation sequencing and chromosomal microarray have advanced the understanding of the molecular pathogenesis of a variety of renal disorders. Genetic findings are increasingly used to inform the clinical management of many nephropathies, enabling targeted disease surveillance, choice of therapy, and family counselling. Genetic analysis has excellent diagnostic utility in paediatric nephrology, as illustrated by sequencing studies of patients with congenital anomalies of the kidney and urinary tract and steroid-resistant nephrotic syndrome. Although additional investigation is needed, pilot studies suggest that genetic testing can also provide similar diagnostic insight among adult patients. Reaching a genetic diagnosis first involves choosing the appropriate testing modality, as guided by the clinical presentation of the patient and the number of potential genes associated with the suspected nephropathy. Genome-wide sequencing increases diagnostic sensitivity relative to targeted panels, but holds the challenges of identifying causal variants in the vast amount of data generated and interpreting secondary findings. In order to realize the promise of genomic medicine for kidney disease, many technical, logistical, and ethical questions that accompany the implementation of genetic testing in nephrology must be addressed. The creation of evidence-based guidelines for the utilization and implementation of genetic testing in nephrology will help to translate genetic knowledge into improved clinical outcomes for patients with kidney disease.

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Figure 1: The genomic nephrology workflow: genetic diagnosis and clinical application.

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Acknowledgements

The work of the authors was supported by grants from the US National Institutes of Health (1F30DK116473 (E.E.G.), 2R01DK080099, and 5U01HG008680 (A.G.G.)), and the American Society of Nephrology Foundation for Kidney Research Donald E. Wesson Research Fellowship (H.M.R.).

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Contributions

All authors contributed substantially to the research and writing process, including discussing the content of the article and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Ali G. Gharavi.

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PowerPoint slides

Glossary

Heritability

The proportion of interindividual variation in a given trait that is due to genetic factors.

Chromosomal microarray

(CMA). A technique to detect copy number variants by hybridizing a patient's DNA to probes corresponding to various regions of the genome; the hybridization pattern for a given probe reflects the number of copies that the patient has of that genomic region.

Next-generation sequencing

(NGS). Simultaneous sequencing of multiple DNA segments; also known as massively parallel sequencing.

Genome

The entirety of an individual's DNA. The genome is divided into smaller protein-coding segments called genes.

Genetic testing

The assessment of DNA sequence variation. Genetic testing can be performed at the level of a single variant, a gene, multiple genes, or the entire genome.

Genomic medicine

An emerging branch of medicine that uses information about an individual's genome to inform their clinical care, including diagnosis, prognosis, and treatment.

Genetic diagnosis

The hereditary aetiology of a patient's presentation, as identified by genetic testing.

Single-nucleotide variants

(SNVs). Changes of single bases (nucleotides) in a DNA sequence. SNVs can lead to an altered amino acid sequence in the encoded protein (nonsynonymous variants) or leave the sequence unchanged (synonymous variants).

Insertions or deletions

The gain or loss of bases in a DNA sequence, resulting in an altered amino acid sequence in the encoded protein.

Structural variants

Large (≥1 kb) DNA variants that include balanced (for example, inversions or reciprocal translocations) and imbalanced alterations (for example, copy number variants).

Sanger sequencing

A DNA sequencing method that uses labelled chain-terminating dideoxynucleotides to identify the nucleotides in the DNA strand being sequenced. This method generates a sequence chromatogram that can be analysed to detect genetic variants.

Targeted next-generation sequencing panels

Next-generation-sequencing-based analysis of a set of genes commonly associated with the patient's clinically suspected phenotype.

Whole-exome sequencing

(WES). Next-generation-sequencing-based analysis of the exome — the protein-coding regions of the genome that contain the majority of known causal variants for Mendelian disorders.

Whole-genome sequencing

(WGS). Next-generation-sequencing-based analysis of the whole genome, including protein-coding and non-coding regions.

Karyotyping

A technique used to detect large genomic imbalances through visual inspection of stained chromosomes using a microscope at high magnification (×1,000).

Copy number variants

(CNVs). Structural variants that results in gain or loss of DNA at the relevant locus.

Array comparative genomic hybridization

A type of chromosomal microarray in which patient and control DNA are labelled with different coloured fluorescent dyes and cohybridized to a single DNA probe in order to directly compare copy number at that genomic region.

Single-nucleotide polymorphism arrays

A type of chromosomal microarray in which a patient's DNA is hybridized to DNA probes corresponding to single-nucleotide polymorphisms and the hybridization pattern is compared with previously analysed controls. This type of chromosomal microarray can detect a patient's genotype in addition to copy number at a given genomic region.

Balanced chromosomal rearrangements

Chromosomal rearrangements that do not cause a net loss or gain of genetic material.

Sequencing coverage and depth

In this Review, sequencing coverage denotes the percentage of bases in the DNA region targeted by sequencing that is sequenced a given number of times. Sequencing depth refers to the average number of times that a given nucleotide is read in a set of DNA sequence reads. Higher coverage and depth means that more of the targeted genomic region has been sampled a greater number of times, increasing the accuracy of the resulting data.

Secondary findings

Genetic findings that are not related to the primary indication for testing; also called incidental findings.

Multiplex ligation-dependent probe amplification

A technique in which patient DNA is hybridized to two oligonucleotide probes, corresponding to the 5′ and 3′ ends of the DNA, which are then ligated and PCR-amplified using a fluorescently labelled primer. The resulting PCR products are size-separated using capillary electrophoresis, and the fluorescent signal intensity is compared between the probe and the patient's DNA to determine copy number at that region. In addition to identifying copy number variants, this technique can detect mosaicism for a copy number variant and DNA methylation status.

Variants of uncertain significance

(VUSs). Genetic variants that have an unclear association with a given disorder owing to insufficient or conflicting evidence.

Phenotypic expansions

Phenotypic expansions occur when mutations in a gene that is classically associated with one phenotype are demonstrated to cause another clinically distinct phenotype.

Allele

Within each chromosome, the DNA sequence at a given region can vary; these variants are alleles.

Missense variant

Single-nucleotide variant that leads to the replacement of the amino acid normally encoded with another amino acid.

Haploinsufficiency

The state that arises when one copy of a gene is deleted or otherwise inactivated and the single remaining copy is insufficient to produce the amount of gene product needed to maintain normal function, leading to an abnormal (disease) phenotype.

Loss-of-function variation

DNA sequence alteration that leads to a protein with severely reduced or no function. Genetic variants that result in a prematurely truncated protein, such as nonsense variants, generally cause loss of function; however, missense variants can also have this effect.

Nonsense variant

Single-nucleotide variant that leads to the replacement of the amino acid normally encoded with a stop codon, leading to a prematurely truncated protein.

Variant phasing

Determining whether two variants in an individual's genome are both on the same copy of the gene (in cis) or on different copies of the genes (in trans) by use of parental testing. If two variants in a gene associated with a recessive disorder are in trans, they are more likely to be causal for the disorder, as they will impact both copies of the gene.

Allele frequency

The incidence of an allele in a population. Allele frequency is calculated by dividing the number of times that the allele is found by the total number of chromosomes. The allele frequency can be used to assess the rarity of a certain allele to help ascertain its pathogenicity during clinical sequence interpretation.

Penetrance

The proportion of individuals with a certain genetic variant who display the phenotype that is associated with this variant.

Genetic discrimination

(GD). Differential treatment of individuals on the basis of their genetic information.

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Groopman, E., Rasouly, H. & Gharavi, A. Genomic medicine for kidney disease. Nat Rev Nephrol 14, 83–104 (2018). https://doi.org/10.1038/nrneph.2017.167

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