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
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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Devuyst, O. et al. Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet 383, 1844–1859 (2014). This review provides a comprehensive overview of the major Mendelian forms of CKD and examines the existing challenges to and future opportunities for effective clinical detection and management.
Jha, V. et al. Chronic kidney disease: global dimension and perspectives. Lancet 382, 260–272 (2013).
Wuhl, E. et al. Renal replacement therapy for rare diseases affecting the kidney: an analysis of the ERA-EDTA Registry. Nephrol. Dial. Transplant. 29 (Suppl. 4), iv1–iv8 (2014).
Vivante, A. & Hildebrandt, F. Exploring the genetic basis of early-onset chronic kidney disease. Nat. Rev. Nephrol. 12, 133–146 (2016).
Ingelfinger, J. R., Kalantar-Zadeh, K., Schaefer, F. & World Kidney Day Steering Committee. World Kidney Day 2016: averting the legacy of kidney disease — focus on childhood. Pediatr. Nephrol. 31, 343–348 (2016).
Arpegard, J. et al. Comparison of heritability of Cystatin C− and creatinine-based estimates of kidney function and their relation to heritability of cardiovascular disease. J. Am. Heart Assoc. 4, e001467 (2015).
Fox, C. S. et al. Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J. Am. Soc. Nephrol. 15, 2457–2461 (2004).
Moulin, F. et al. A population-based approach to assess the heritability and distribution of renal handling of electrolytes. Kidney Int. 92, 1536–1543 (2017).
Wilmot, B. et al. Heritability of serum sodium concentration: evidence for sex- and ethnic-specific effects. Physiol. Genomics 44, 220–228 (2012).
Lieske, J. C., Turner, S. T., Edeh, S. N., Smith, J. A. & Kardia, S. L. Heritability of urinary traits that contribute to nephrolithiasis. Clin. J. Am. Soc. Nephrol. 9, 943–950 (2014).
Skrunes, R., Svarstad, E., Reisaeter, A. V. & Vikse, B. E. Familial clustering of ESRD in the Norwegian population. Clin. J. Am. Soc. Nephrol. 9, 1692–1700 (2014).
Connaughton, D. M. et al. The Irish Kidney Gene Project — prevalence of family history in patients with kidney disease in Ireland. Nephron 130, 293–301 (2015).
McClellan, W. M. et al. Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities. Am. J. Kidney Dis. 53, S100–S106 (2009).
Joly, D., Beroud, C. & Grunfeld, J. P. Rare inherited disorders with renal involvement-approach to the patient. Kidney Int. 87, 901–908 (2015).
Liapis, H. & Gaut, J. P. The renal biopsy in the genomic era. Pediatr. Nephrol. 28, 1207–1219 (2013).
Australia and New Zealand Dialysis and Transplant Registry. Annual ANZDATA Report (ANZDATA Registry, South Adelaide, Australia, 2016).
European Renal Association–European Dialysis and Transplant Association. ERA-EDTA Annual Report 2015. ERA-EDTA Registry https://www.era-edta-reg.org/files/annualreports/pdf/AnnRep2015.pdf (2017).
United States Renal Data System. USRDS annual data report: epidemiology of kidney disease in the United States (National Institutes of Health, 2017).
James, M. T., Hemmelgarn, B. R. & Tonelli, M. Early recognition and prevention of chronic kidney disease. Lancet 375, 1296–1309 (2010).
KDIGO. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 19–62 (2013).
Chong, J. X. et al. The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities. Am. J. Hum. Genet. 97, 199–215 (2015).
Smith, L. D., Willig, L. K. & Kingsmore, S. F. Whole-exome sequencing and whole-genome sequencing in critically ill neonates suspected to have single-gene disorders. Cold Spring Harb. Perspect. Med. 6, a023168 (2015).
Miller, D. T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764 (2010).
Guttmacher, A. E. & Collins, F. S. Genomic medicine — a primer. N. Engl. J. Med. 347, 1512–1520 (2002).
Dixon-Salazar, T. J. et al. Exome sequencing can improve diagnosis and alter patient management. Sci. Transl Med. 4, 138ra178 (2012).
Lee, H. et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312, 1880–1887 (2014).
Valencia, C. A. et al. Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a Pediatric Center's Experience. Front. Pediatr. 3, 67 (2015).
Stokman, M. F. et al. The expanding phenotypic spectra of kidney diseases: insights from genetic studies. Nat. Rev. Nephrol. 12, 472–483 (2016).
Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Online Mendelian Inheritance in Man. OMIM Gene Map Statistics. OMIM https://www.omim.org/statistics/geneMap (2017).
Goldstein, D. B. et al. Sequencing studies in human genetics: design and interpretation. Nat. Rev. Genet. 14, 460–470 (2013).
Katsanis, S. H. & Katsanis, N. Molecular genetic testing and the future of clinical genomics. Nat. Rev. Genet. 14, 415–426 (2013).
Rehm, H. L. Disease-targeted sequencing: a cornerstone in the clinic. Nat. Rev. Genet. 14, 295–300 (2013).
Petersen, B. S., Fredrich, B., Hoeppner, M. P., Ellinghaus, D. & Franke, A. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet. 18, 14 (2017).
Xue, Y., Ankala, A., Wilcox, W. R. & Hegde, M. R. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet. Med. 17, 444–451 (2015). This review compares the major diagnostic genetic testing modalities and provides a generalized algorithm to help select the most appropriate test given a patient's clinical presentation.
Carvalho, C. M. & Lupski, J. R. Mechanisms underlying structural variant formation in genomic disorders. Nat. Rev. Genet. 17, 224–238 (2016).
Watson, C. T., Marques-Bonet, T., Sharp, A. J. & Mefford, H. C. The genetics of microdeletion and microduplication syndromes: an update. Annu. Rev. Genomics Hum. Genet. 15, 215–244 (2014).
Carter, N. P. Methods and strategies for analyzing copy number variation using DNA microarrays. Nat. Genet. 39, S16–S21 (2007).
Schaaf, C. P., Wiszniewska, J. & Beaudet, A. L. Copy number and SNP arrays in clinical diagnostics. Annu. Rev. Genomics Hum. Genet. 12, 25–51 (2011).
Vermeesch, J. R., Brady, P. D., Sanlaville, D., Kok, K. & Hastings, R. J. Genome-wide arrays: quality criteria and platforms to be used in routine diagnostics. Hum. Mutat. 33, 906–915 (2012).
Kearney, H. M. et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet. Med. 13, 680–685 (2011).
Reddy, U. M. et al. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N. Engl. J. Med. 367, 2185–2193 (2012).
Wapner, R. J. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 367, 2175–2184 (2012).
South, S. T. et al. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet. Med. 15, 901–909 (2013).
Pinto, D. et al. Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat. Biotechnol. 29, 512–520 (2011).
Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nat. Rev. Genet. 12, 363–376 (2011).
Harambat, J., van Stralen, K. J., Kim, J. J. & Tizard, E. J. Epidemiology of chronic kidney disease in children. Pediatr. Nephrol. 27, 363–373 (2012).
Nicolaou, N., Renkema, K. Y., Bongers, E. M., Giles, R. H. & Knoers, N. V. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat. Rev. Nephrol. 11, 720–731 (2015).
Weber, S. et al. Mapping candidate regions and genes for congenital anomalies of the kidneys and urinary tract (CAKUT) by array-based comparative genomic hybridization. Nephrol. Dial. Transplant. 26, 136–143 (2011).
Sanna-Cherchi, S. et al. Copy-number disorders are a common cause of congenital kidney malformations. Am. J. Hum. Genet. 91, 987–997 (2012).
Tammimies, K. et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA 314, 895–903 (2015).
Caruana, G. et al. Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatr. Nephrol. 30, 487–495 (2015).
Faure, A. et al. DNA copy number variants: a potentially useful predictor of early onset renal failure in boys with posterior urethral valves. J. Pediatr. Urol. 12, 227.e1–227.e7 (2016).
Westland, R. et al. Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney Int. 88, 1402–1410 (2015).
Verbitsky, M. et al. Genomic imbalances in pediatric patients with chronic kidney disease. J. Clin. Invest. 125, 2171–2178 (2015).
Fu, F. et al. Prenatal diagnosis of fetal multicystic dysplastic kidney via high-resolution whole-genome array. Nephrol. Dial. Transplant. 31, 1693–1698 (2016).
Moreira, J. M., Bouissou Morais Soares, C. M., Teixeira, A. L., Simoes, E. S. A. C. & Kummer, A. M. Anxiety, depression, resilience and quality of life in children and adolescents with pre-dialysis chronic kidney disease. Pediatr. Nephrol. 30, 2153–2162 (2015).
Hooper, S. R. et al. Neurocognitive functioning of children and adolescents with mild-to-moderate chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 1824–1830 (2011).
Ruebner, R. L. et al. Neurocognitive dysfunction in children, adolescents, and young adults with CKD. Am. J. Kidney Dis. 67, 567–575 (2016).
Verbitsky, M. et al. Genomic disorders and neurocognitive impairment in pediatric CKD. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.2016101108 (2017). This article shows that paediatric patients with CKD owing to genomic disorders have poorer neurocognitive function than those without independent of the severity of renal dysfunction. These results suggest that for some patients, neurocognitive impairment and nephropathy have a common genetic basis, informing clinical expectations and management.
Goodwin, S., McPherson, J. D. & McCombie, W. R. Coming of age: ten years of next-generation sequencing technologies. Nat. Rev. Genet. 17, 333–351 (2016). This Review provides an excellent technical summary of existing and emerging NGS-based approaches for genomic sequencing.
Levy, S. E. & Myers, R. M. Advancements in next-generation sequencing. Annu. Rev. Genomics Hum. Genet. 17, 95–115 (2016).
Rehm, H. L. Evolving health care through personal genomics. Nat. Rev. Genet. 18, 259–267 (2017). This Review highlights the different uses of genetic testing to achieve personalized health care in a range of clinical contexts and discusses key challenges to broadly implementing genomics into everyday medical practice.
Ashley, E. A. Towards precision medicine. Nat. Rev. Genet. 17, 507–522 (2016).
Chakravorty, S. & Hegde, M. Gene and variant annotation for mendelian disorders in the era of advanced sequencing technologies. Annu. Rev. Genomics Hum. Genet. 18, 229–256 (2017).
Rehm, H. L. et al. ACMG clinical laboratory standards for next-generation sequencing. Genet. Med. 15, 733–747 (2013).
Wallis, Y. et al. Practice Guidelines for the Evaluation of Pathogenicity and the Reporting of Sequence Variants in Clinical Molecular Genetics (Association for Clinical Genetic Science, 2013).
Matthijs, G. et al. Guidelines for diagnostic next-generation sequencing. Eur. J. Hum. Genet. 24, 2–5 (2016).
Shashi, V. et al. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet. Med. 16, 176–182 (2014).
Sadowski, C. E. et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1279–1289 (2015).
McCarthy, H. J. et al. Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 8, 637–648 (2013).
Braun, D. A. et al. Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin. J. Am. Soc. Nephrol. 11, 664–672 (2016).
Halbritter, J. et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J. Am. Soc. Nephrol. 26, 543–551 (2015).
Schueler, M. et al. Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies. J. Med. Genet. 53, 208–214 (2016).
Halbritter, J. et al. High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing. J. Med. Genet. 49, 756–767 (2012).
Hwang, D. Y. et al. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 85, 1429–1433 (2014).
Kohl, S. et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 25, 1917–1922 (2014).
Gross, O. et al. Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome. Nephrol. Dial. Transplant. 32, 916–924 (2017).
Savige, J. et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J. Am. Soc. Nephrol. 24, 364–375 (2013).
Moriniere, V. et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J. Am. Soc. Nephrol. 25, 2740–2751 (2014).
Nicolaou, N. et al. Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT. Kidney Int. 89, 476–486 (2016).
Heidet, L. et al. Targeted exome sequencing identifies PBX1 as involved in monogenic congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 28, 2901–2914 (2017).
Delio, M. et al. Development of a targeted multi-disorder high-throughput sequencing assay for the effective identification of disease-causing variants. PLoS ONE 10, e0133742 (2015).
Saudi Mendeliome, G. Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases. Genome Biol. 16, 134 (2015).
Zemojtel, T. et al. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci. Transl Med. 6, 252ra123 (2014).
Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745–755 (2011).
Gilissen, C., Hoischen, A., Brunner, H. G. & Veltman, J. A. Disease gene identification strategies for exome sequencing. Eur. J. Hum. Genet. 20, 490–497 (2012).
Eldomery, M. K. et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome Med. 9, 26 (2017).
Wenger, A. M., Guturu, H., Bernstein, J. A. & Bejerano, G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet. Med. 19, 209–214 (2016). This study identified newly diagnostic mutations in 10% of patients with initially nondiagnostic WES results, highlighting the importance of regular sequence reanalysis in clinical testing.
Need, A. C., Shashi, V., Schoch, K., Petrovski, S. & Goldstein, D. B. The importance of dynamic re-analysis in diagnostic whole exome sequencing. J. Med. Genet. 54, 155–156 (2017).
Bowling, K. M. et al. Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med. 9, 43 (2017).
LaDuca, H. et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS ONE 12, e0170843 (2017).
Mandelker, D. et al. Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. Genet. Med. 18, 1282–1289 (2016).
Park, J. Y. et al. Clinical exome performance for reporting secondary genetic findings. Clin. Chem. 61, 213–220 (2015).
Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33 (Suppl.), 228–237 (2003).
Cooper, D. N. et al. Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum. Mutat. 31, 631–655 (2010).
Boycott, K. M., Vanstone, M. R., Bulman, D. E. & MacKenzie, A. E. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14, 681–691 (2013).
Ku, C. S., Naidoo, N. & Pawitan, Y. Revisiting Mendelian disorders through exome sequencing. Hum. Genet. 129, 351–370 (2011).
Taylor, J. C. et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat. Genet. 47, 717–726 (2015).
Lupski, J. R. et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N. Engl. J. Med. 362, 1181–1191 (2010).
Saunders, C. J. et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci. Transl Med. 4, 154ra135 (2012).
Yuen, R. K. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat. Med. 21, 185–191 (2015).
Mele, C. et al. Characterization of a new DGKE intronic mutation in genetically unsolved cases of familial atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 10, 1011–1019 (2015).
King, K., Flinter, F. A., Nihalani, V. & Green, P. M. Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum. Genet. 111, 548–554 (2002).
Carroll, C., Hunley, T. E., Guo, Y. & Cortez, D. A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia. Am. J. Med. Genet. A 167A, 2260–2264 (2015).
Lo, Y. F. et al. Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. Clin. J. Am. Soc. Nephrol. 6, 630–639 (2011).
Cabezas, O. R. et al. Polycystic kidney disease with hyperinsulinemic hypoglycemia caused by a promoter mutation in phosphomannomutase 2. J. Am. Soc. Nephrol. 28, 2529–2539 (2017).
Belkadi, A. et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc. Natl Acad. Sci. USA 112, 5473–5478 (2015).
Lelieveld, S. H., Spielmann, M., Mundlos, S., Veltman, J. A. & Gilissen, C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum. Mutat. 36, 815–822 (2015).
Mallawaarachchi, A. C. et al. Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur. J. Hum. Genet. 24, 1584–1590 (2016).
Watson, C. M. et al. Enhanced diagnostic yield in Meckel–Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping. BMC Med. Genet. 17, 1 (2016).
Carss, K. J. et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am. J. Hum. Genet. 100, 75–90 (2017).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Stavropoulos, D. J. et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genomics Med. 1, 15012 (2016).
Kirby, A. et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat. Genet. 45, 299–303 (2013).
Blumenstiel, B. et al. Development and validation of a mass spectrometry-based assay for the molecular diagnosis of mucin-1 kidney disease. J. Mol. Diagn. 18, 566–571 (2016).
Dewey, F. E. et al. Clinical interpretation and implications of whole-genome sequencing. JAMA 311, 1035–1045 (2014). This article demonstrates the technical and interpretative challenges of using WGS in a clinical setting, highlighting key priorities to be addressed in order for this modality to be employed in patient care.
Chrystoja, C. C. & Diamandis, E. P. Whole genome sequencing as a diagnostic test: challenges and opportunities. Clin. Chem. 60, 724–733 (2014).
Braun, D. A. & Hildebrandt, F. Ciliopathies. Cold Spring Harb. Perspect. Biol. 9, a028191 (2017).
Renkema, K. Y., Stokman, M. F., Giles, R. H. & Knoers, N. V. Next-generation sequencing for research and diagnostics in kidney disease. Nat. Rev. Nephrol. 10, 433–444 (2014).
Halbritter, J. et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum. Genet. 132, 865–884 (2013).
Braun, D. A. et al. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. Kidney Int. 89, 468–475 (2016).
Gee, H. Y. et al. Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int. 85, 880–887 (2014).
Bierzynska, A. et al. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int. 91, 937–947 (2017).
Heyer, C. M. et al. Predicted mutation strength of nontruncating PKD1 mutations aids genotype–phenotype correlations in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 27, 2872–2884 (2016).
Audrezet, M. P. et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum. Mutat. 33, 1239–1250 (2012).
Gunay-Aygun, M. et al. PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis. Mol. Genet. Metab. 99, 160–173 (2010).
Krall, P. et al. Cost-effective PKHD1 genetic testing for autosomal recessive polycystic kidney disease. Pediatr. Nephrol. 29, 223–234 (2014).
Porath, B. et al. Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am. J. Hum. Genet. 98, 1193–1207 (2016).
Lu, H. et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat. Genet. 49, 1025–1034 (2017).
Gast, C. et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol. Dial. Transplant. 31, 961–970 (2016).
Malone, A. F. et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 86, 1253–1259 (2014).
Verhave, J. C., Bech, A. P., Wetzels, J. F. & Nijenhuis, T. Hepatocyte nuclear factor 1beta-associated kidney disease: more than renal cysts and diabetes. J. Am. Soc. Nephrol. 27, 345–353 (2016).
Clissold, R. L., Hamilton, A. J., Hattersley, A. T., Ellard, S. & Bingham, C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat. Rev. Nephrol. 11, 102–112 (2015).
Barua, M. et al. Mutations in PAX2 associate with adult-onset FSGS. J. Am. Soc. Nephrol. 25, 1942–1953 (2014).
Huynh Cong, E. et al. A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS. J. Am. Soc. Nephrol. 25, 2435–2443 (2014).
Bullich, G. et al. Contribution of the TTC21B gene to glomerular and cystic kidney diseases. Nephrol. Dial. Transplant. 32, 151–156 (2017).
Scolari, F., Izzi, C. & Ghiggeri, G. M. Uromodulin: from monogenic to multifactorial diseases. Nephrol. Dial. Transplant. 30, 1250–1256 (2015).
Besbas, N., Ozaltin, F., Jeck, N., Seyberth, H. & Ludwig, M. CLCN5 mutation (R347X) associated with hypokalaemic metabolic alkalosis in a Turkish child: an unusual presentation of Dent's disease. Nephrol. Dial. Transplant. 20, 1476–1479 (2005).
Okamoto, T., Tajima, T., Hirayama, T. & Sasaki, S. A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5. Eur. J. Pediatr. 171, 401–404 (2012).
Fervenza, F. C. A patient with nephrotic-range proteinuria and focal global glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 8, 1979–1987 (2013).
Frishberg, Y. et al. Dent's disease manifesting as focal glomerulosclerosis: is it the tip of the iceberg? Pediatr. Nephrol. 24, 2369–2373 (2009).
Demoulin, N. et al. Gitelman syndrome and glomerular proteinuria: a link between loss of sodium-chloride cotransporter and podocyte dysfunction? Nephrol. Dial. Transplant. 29 (Suppl. 4), iv117–iv120 (2014).
Hanevold, C., Mian, A. & Dalton, R. C1q nephropathy in association with Gitelman syndrome: a case report. Pediatr. Nephrol. 21, 1904–1908 (2006).
Blanchard, A. et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 91, 24–33 (2017).
Lata, S. et al. Whole exome sequencing in adults with chronic kidney disease: a pilot study. Ann. Intern. Med. https://doi.org/10.7326/M17-1319 (2017).
Soden, S. E. et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci. Transl Med. 6, 265ra168 (2014).
Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009). This article is among the first papers published showing the utility of WES to achieve a specific diagnosis for patients presenting with nondiagnostic phenotypes.
Wuttke, M. et al. A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy. Clin. Kidney J. 8, 690–694 (2015).
Nakata, T. et al. Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation. BMC Nephrol. 18, 100 (2017).
Isnard, P. et al. Karyomegalic interstitial nephritis: a case report and review of the literature. Medicine 95, e3349 (2016).
Vivante, A. et al. Exome sequencing discerns syndromes in patients from consanguineous families with congenital anomalies of the kidneys and urinary tract. J. Am. Soc. Nephrol. 28, 69–75 (2017). This article describes the successful use of WES to achieve a molecular diagnosis in genetically unresolved cases of CAKUT. Notably, 44% of diagnosed patients had mutations in genes not classically associated with CAKUT, highlighting the utility of genome-wide testing to pinpoint a specific — and often unexpected — disease aetiology among patients with nonspecific phenotypes.
Bockenhauer, D. & Bichet, D. G. Urinary concentration: different ways to open and close the tap. Pediatr. Nephrol. 29, 1297–1303 (2014).
Emma, F. et al. Nephropathic cystinosis: an international consensus document. Nephrol. Dial. Transplant. 29 (Suppl. 4), iv87–iv94 (2014).
Cochat, P. & Rumsby, G. Primary hyperoxaluria. N. Engl. J. Med. 369, 649–658 (2013).
Aymé, S. et al. Common elements in rare kidney diseases: conclusions from a kidney disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 92, 796–808 (2017).
Savige, J. et al. Alport syndrome in women and girls. Clin. J. Am. Soc. Nephrol. 11, 1713–1720 (2016).
Wang, R. Y., Lelis, A., Mirocha, J. & Wilcox, W. R. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet. Med. 9, 34–45 (2007).
Terryn, W. et al. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol. Dial. Transplant. 28, 505–517 (2013).
Lentine, K. L. et al. KDIGO clinical practice guideline on the evaluation and care of living kidney donors. Transplantation 101, S1–S109 (2017).
Cornec-Le Gall, E. et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrol. 24, 1006–1013 (2013).
Hwang, Y. H. et al. Refining genotype–phenotype correlation in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 27, 1861–1868 (2016).
Gunay-Aygun, M. et al. Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease. Mol. Genet. Metab. 104, 677–681 (2011).
Zhang, J. et al. Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit. Am. J. Physiol. Renal Physiol. 307, F1063–F1071 (2014).
Edwards, N. et al. A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'. Clin. Kidney J. 8, 113–119 (2015).
Munch, J., Grohmann, M., Lindner, T. H., Bergmann, C. & Halbritter, J. Diagnosing FSGS without kidney biopsy — a novel INF2-mutation in a family with ESRD of unknown origin. BMC Med. Genet. 17, 73 (2016).
Ellingford, J. M. et al. Pinpointing clinical diagnosis through whole exome sequencing to direct patient care: a case of Senior-Loken syndrome. Lancet 385, 1916 (2015). This case report illustrates the potential of genetic testing for early diagnosis in a patient with undetected CKD, enabling preplanned initiation of dialysis, appropriate donor selection for renal transplantation, and surveillance of family members at risk.
Quaglia, M. et al. Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy. Clin. Transplant. 28, 995–1003 (2014). This retrospective study of 911 renal transplant recipients highlights the fact that many patients who progress to ESRD have no clear clinical diagnosis of their renal disease and that rare monogenic forms of nephropathy may be found in a notable fraction of these patients. These findings highlight the potential utility of genetic diagnostics for cases of CKD of unknown aetiology.
Berg, J. S. Genome-scale sequencing in clinical care: establishing molecular diagnoses and measuring value. JAMA 312, 1865–1867 (2014).
Lazaridis, K. N. et al. Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine clinic: the Mayo Clinic Experience. Mayo Clin. Proc. 91, 297–307 (2016).
ACMG Board of Directors. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet. Med. 17, 505–507 (2015).
Parker, S. The pooling of manpower and resources through the establishment of European reference networks and rare disease patient registries is a necessary area of collaboration for rare renal disorders. Nephrol. Dial. Transplant. 29 (Suppl. 4), iv9–iv14 (2014).
European Reference Networks. ERKNet: The European Rare Kidney Disease Reference Network. ERKNet https://www.erknet.org/index.php?id=home (2017).
Krischer, J. P., Gopal-Srivastava, R., Groft, S. C., Eckstein, D. J. & Rare Diseases Clinical Research Network. The Rare Diseases Clinical Research Network's organization and approach to observational research and health outcomes research. J. Gen. Intern. Med. 29 (Suppl. 3), S739–S744 (2014).
UK Kidney Research Consortium. Establishing an infrastructure to support the development and delivery of clinical research in patients with kidney disease. Clin. Med. (Lond.) 15, 415–419 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02855268 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02795325 (2016).
Alport Syndrome Foundation. AlportSyndrome.org http://alportsyndrome.org/ (2017).
PKD Foundation. PKDCure.org https://pkdcure.org/ (2017).
UKD Foundation. UKDCure.org http://www.ukdcure.org/ (2017).
Hodson, E. M., Wong, S. C., Willis, N. S. & Craig, J. C. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst. Rev. 10, CD003594 (2016).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015). In this article, the American College of Medical Genetics puts forth guidelines for diagnostic sequence interpretation. The lines of evidence and variant classification scheme discussed offer a helpful framework to assess variant pathogenicity; the authors also discuss the importance of integrating a patient's genetic and clinical data to achieve a genetic diagnosis.
MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014). This article provides general standards for sequence interpretation at both the gene level and variant level and emphasizes the importance of using quantitative methods to enable more accurate and reproducible genetic assessment.
Strande, N. T. & Berg, J. S. Defining the clinical value of a genomic diagnosis in the era of next-generation sequencing. Annu. Rev. Genomics Hum. Genet. 17, 303–332 (2016).
Parsa, A. et al. Common variants in Mendelian kidney disease genes and their association with renal function. J. Am. Soc. Nephrol. 24, 2105–2117 (2013).
Clemente, M. et al. Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene. Endocrinol. Diabetes Metab. Case Rep. 2017, 16–0133 (2017).
Hamilton, A. J. et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a beta cell phenotype. J. Med. Genet. 51, 165–169 (2014).
Bekheirnia, M. R. et al. Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene. Genet. Med. 19, 412–420 (2016).
Jiang, S. et al. Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity. Kidney Int. 66, 10–19 (2004).
Kelly, H. et al. Uroplakin III is not a major candidate gene for primary vesicoureteral reflux. Eur. J. Hum. Genet. 13, 500–502 (2005).
Hennekam, R. C. & Biesecker, L. G. Next-generation sequencing demands next-generation phenotyping. Hum. Mutat. 33, 884–886 (2012).
Shashi, V. et al. Practical considerations in the clinical application of whole-exome sequencing. Clin. Genet. 89, 173–181 (2016).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Cassa, C. A., Tong, M. Y. & Jordan, D. M. Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. Hum. Mutat. 34, 1216–1220 (2013).
Piton, A., Redin, C. & Mandel, J. L. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am. J. Hum. Genet. 93, 368–383 (2013).
Shearer, A. E. et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am. J. Hum. Genet. 95, 445–453 (2014).
Abdelhak, S. et al. Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. Hum. Mol. Genet. 6, 2247–2255 (1997).
Chang, E. H. et al. Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum. Mutat. 23, 582–589 (2004).
NM_000503.5(EYA1):c.1460C>T (p.Ser487Leu). ClinVar https://www.ncbi.nlm.nih.gov/clinvar/variation/228678/#clinical-assertions (2017).
Smith, R. J. H. Branchiootorenal spectrum disorders. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1380 (2015).
Amendola, L. M. et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am. J. Hum. Genet. 98, 1067–1076 (2016).
Yang, S. et al. Sources of discordance among germ-line variant classifications in ClinVar. Genet. Med. 19, 1118–1126 (2017).
Safarova, M. S. et al. Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. Eur. J. Hum. Genet. 25, 410–415 (2017).
Harrison, S. M. et al. Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. Genet. Med. 19, 1096–1104 (2017).
Strande, N. T. et al. Evaluating the clinical validity of gene–disease associations: an evidence-based framework developed by the Clinical Genome Resource. Am. J. Hum. Genet. 100, 895–906 (2017).
Patel, R. Y. et al. ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants. Genome Med. 9, 3 (2017).
Li, Q. & Wang, K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am. J. Hum. Genet. 100, 267–280 (2017).
Knoppers, B. M., Zawati, M. H. & Senecal, K. Return of genetic testing results in the era of whole-genome sequencing. Nat. Rev. Genet. 16, 553–559 (2015).
Demmer, L. A. & Waggoner, D. J. Professional medical education and genomics. Annu. Rev. Genomics Hum. Genet. 15, 507–516 (2014).
Meagher, K. M., McGowan, M. L., Settersten, R. A., Fishman, J. R. & Juengst, E. T. Precisely where are we going? Charting the new terrain of precision prevention. Annu. Rev. Genomics Hum. Genet. 18, 369–387 (2017). This review examines central ELSIs of expanding genetic testing to a population-wide scale and highlights the need for study of both genetic and environmental determinants of health.
Berg, J. S., Khoury, M. J. & Evans, J. P. Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time. Genet. Med. 13, 499–504 (2011).
Burke, W. Genetic tests: clinical validity and clinical utility. Curr. Protoc. Hum. Genet. 81, 9.15.1–9.15.8 (2014).
Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).
Kalia, S. S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet. Med. 19, 249–255 (2017).
van El, C. G. et al. Whole-genome sequencing in health care: recommendations of the European Society of Human Genetics. Eur. J. Hum. Genet. 21, 580–584 (2013).
Amendola, L. M. et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 25, 305–315 (2015).
Olfson, E. et al. Identification of medically actionable secondary findings in the 1000 Genomes. PLoS ONE 10, e0135193 (2015).
Birdwell, K. A. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin. Pharmacol. Ther. 98, 19–24 (2015).
Relling, M. V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin. Pharmacol. Ther. 89, 387–391 (2011).
Hunter, J. E. et al. A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation. Genet. Med. 18, 1258–1268 (2016). This article gives a systematic workflow to assess the medical actionability of a given genetic disease, which can be used to help determine which results may merit return as medically actionable secondary findings.
O'Daniel, J. M. et al. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet. Med. 19, 575–582 (2017).
Otten, E. et al. Is there a duty to recontact in light of new genetic technologies? A systematic review of the literature. Genet. Med. 17, 668–678 (2015).
Pyeritz, R. E. The coming explosion in genetic testing — is there a duty to recontact? N. Engl. J. Med. 365, 1367–1369 (2011).
ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet. Med. 14, 759–761 (2012).
Shahmirzadi, L. et al. Patient decisions for disclosure of secondary findings among the first 200 individuals undergoing clinical diagnostic exome sequencing. Genet. Med. 16, 395–399 (2014).
Delikurt, T., Williamson, G. R., Anastasiadou, V. & Skirton, H. A systematic review of factors that act as barriers to patient referral to genetic services. Eur. J. Hum. Genet. 23, 739–745 (2015).
Cichon, M. & Feldman, G. L. Opportunities to improve recruitment into medical genetics residency programs: survey results of program directors and medical genetics residents. Genet. Med. 16, 413–418 (2014).
Plunkett-Rondeau, J., Hyland, K. & Dasgupta, S. Training future physicians in the era of genomic medicine: trends in undergraduate medical genetics education. Genet. Med. 17, 927–934 (2015).
Berns, J. S. A survey-based evaluation of self-perceived competency after nephrology fellowship training. Clin. J. Am. Soc. Nephrol. 5, 490–496 (2010).
Murray, M. F. Educating physicians in the era of genomic medicine. Genome Med. 6, 45 (2014).
Kentwell, M. et al. Mainstreaming cancer genetics: a model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol. Oncol. 145, 130–136 (2017).
Rhodes, A. et al. Minding the genes: a multidisciplinary approach towards genetic assessment of cardiovascular disease. J. Genet. Couns. 26, 224–231 (2017).
Green, R. C. et al. Clinical Sequencing Exploratory Research Consortium: accelerating evidence-based practice of genomic medicine. Am. J. Hum. Genet. 98, 1051–1066 (2016).
Skirton, H. et al. Genetic education and the challenge of genomic medicine: development of core competences to support preparation of health professionals in Europe. Eur. J. Hum. Genet. 18, 972–977 (2010).
Gross, O. et al. Safety and efficacy of the ACE-inhibitor ramipril in alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr. 2012, 436046 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01485978 (2017).
Dumitrescu, L. et al. Genome-wide study of resistant hypertension identified from electronic health records. PLoS ONE 12, e0171745 (2017).
Facio, F. M. et al. Motivators for participation in a whole-genome sequencing study: implications for translational genomics research. Eur. J. Hum. Genet. 19, 1213–1217 (2011).
Hallowell, N. et al. An investigation of patients' motivations for their participation in genetics-related research. J. Med. Ethics 36, 37–45 (2010).
US Department of Health and Human Services. How does genetic testing in a research setting differ from clinical genetic testing? Genetics Home Reference https://ghr.nlm.nih.gov/primer/testing/researchtesting (2017).
Ferreira-Gonzalez, A. et al. US system of oversight for genetic testing: a report from the Secretary's Advisory Committee on Genetics, Health and Society. Per. Med. 5, 521–528 (2008).
Jarvik, G. P. et al. Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am. J. Hum. Genet. 94, 818–826 (2014). This article discusses the practical and ethical questions surrounding the return of medically actionable results to participants in genomic research studies and gives consensus guidelines to help navigate this complex process.
Aronson, S. J. & Rehm, H. L. Building the foundation for genomics in precision medicine. Nature 526, 336–342 (2015).
Lyon, G. J. Personalized medicine: bring clinical standards to human-genetics research. Nature 482, 300–301 (2012).
Crews, D. C., Liu, Y. & Boulware, L. E. Disparities in the burden, outcomes, and care of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 23, 298–305 (2014).
Patzer, R. E. & McClellan, W. M. Influence of race, ethnicity and socioeconomic status on kidney disease. Nat. Rev. Nephrol. 8, 533–541 (2012).
Webb, B. D. et al. A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population. Clin. Genet. 86, 155–160 (2014).
Verlander, P. C. et al. Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Blood 86, 4034–4038 (1995).
Fedick, A., Jalas, C. & Treff, N. R. A deleterious mutation in the PEX2 gene causes Zellweger syndrome in individuals of Ashkenazi Jewish descent. Clin. Genet. 85, 343–346 (2014).
Friedman, D. J. & Pollak, M. R. Apolipoprotein L1 and kidney disease in African Americans. Trends Endocrinol. Metab. 27, 204–215 (2016).
Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).
Kruzel-Davila, E., Wasser, W. G., Aviram, S. & Skorecki, K. APOL1 nephropathy: from gene to mechanisms of kidney injury. Nephrol. Dial. Transplant. 31, 349–358 (2016).
Kramer, H. J. et al. African ancestry-specific alleles and kidney disease risk in Hispanics/Latinos. J. Am. Soc. Nephrol. 28, 915–922 (2017). This article demonstrates that the APOL1 risk alleles and/or sickle cell trait are associated with increased CKD risk amongst self-reported Hispanic individuals, but their prevalence varies widely between the Caribbean and non-Caribbean subpopulations owing to differences in genetic ancestry. These findings highlight the importance of detailed consideration of genetic ancestry when assessing the impact of sequence variants on disease risk within a population.
Naik, R. P. et al. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 312, 2115–2125 (2014).
Petrovski, S. & Goldstein, D. B. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 17, 157 (2016).
Manrai, A. K. et al. Genetic misdiagnoses and the potential for health disparities. N. Engl. J. Med. 375, 655–665 (2016). This article describes genetic misdiagnoses amongst African-American patients with suspected familial hypertrophic cardiomyopathy, highlighting the importance of interpreting sequence data in the context of patients' genetic ancestry.
Need, A. C. & Goldstein, D. B. Next generation disparities in human genomics: concerns and remedies. Trends Genet. 25, 489–494 (2009).
Popejoy, A. B. & Fullerton, S. M. Genomics is failing on diversity. Nature 538, 161–164 (2016).
Shea, L., Newschaffer, C. J., Xie, M., Myers, S. M. & Mandell, D. S. Genetic testing and genetic counseling among Medicaid-enrolled children with autism spectrum disorder in 2001 and 2007. Hum. Genet. 133, 111–116 (2014).
Hann, K. E. J. et al. Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review. BMC Public Health 17, 503 (2017).
Halbert, C. H., McDonald, J. A., Magwood, G. & Jefferson, M. Beliefs about genetically targeted care in African Americans. J. Natl Med. Assoc. 109, 98–106 (2017).
National Institutes of Health. NIH funds precision medicine research with a focus on health disparities. NIH https://www.nih.gov/news-events/news-releases/nih-funds-precision-medicine-research-focus-health-disparities (2016).
Kingsmore, S. F. et al. Next-generation community genetics for low- and middle-income countries. Genome Med. 4, 25 (2012).
Tekola-Ayele, F. & Rotimi, C. N. Translational genomics in low- and middle-income countries: opportunities and challenges. Public Health Genomics 18, 242–247 (2015).
World Health Organization. Community genetics services: report of a WHO consultation on community genetics in low- and middle-income countries (WHO, 2010).
Obrador, G. T. et al. Genetic and environmental risk factors for chronic kidney disease. Kidney Int. Suppl. 7, 88–106 (2017).
Maltese, P. E. et al.Genetic tests for low- and middle-income countries: a literature review. Genet. Mol. Res. 16, gmr16019466 (2017).
Bogershausen, N. et al. An unusual presentation of Kabuki syndrome with orbital cysts, microphthalmia, and cholestasis with bile duct paucity. Am. J. Med. Genet. A 170A, 3282–3288 (2016).
Moosa, S. et al. Novel IFT122 mutations in three Argentinian patients with cranioectodermal dysplasia: expanding the mutational spectrum. Am. J. Med. Genet. A 170A, 1295–1301 (2016).
Osafo, C. et al. Human Heredity and Health (H3) in Africa Kidney Disease Research Network: a focus on methods in sub-Saharan Africa. Clin. J. Am. Soc. Nephrol. 10, 2279–2287 (2015).
Illumina. H3Africa Consortium Array Available Soon. Illumina https://www.illumina.com/company/news-center/feature-articles/h3africa-consortium-array-available-soon-.html (2016).
Bredenoord, A. L., de Vries, M. C. & van Delden, H. The right to an open future concerning genetic information. Am. J. Bioeth. 14, 21–23 (2014).
Wilfond, B. S., Fernandez, C. V. & Green, R. C. Disclosing secondary findings from pediatric sequencing to families: considering the “benefit to families”. J. Law Med. Eth. 43, 552–558 (2015).
Committee on Bioethics et al. Ethical and policy issues in genetic testing and screening of children. Pediatrics 131, 620–622 (2013).
Ross, L. F. et al. Technical report: ethical and policy issues in genetic testing and screening of children. Genet. Med. 15, 234–245 (2013).
Hufnagel, S. B., Martin, L. J., Cassedy, A., Hopkin, R. J. & Antommaria, A. H. Adolescents' preferences regarding disclosure of incidental findings in genomic sequencing that are not medically actionable in childhood. Am. J. Med. Genet. A 170A, 2083–2088 (2016).
Otlowski, M., Taylor, S. & Bombard, Y. Genetic discrimination: international perspectives. Annu. Rev. Genomics Hum. Genet. 13, 433–454 (2012).
Joly, Y., Feze, I. N., Song, L. & Knoppers, B. M. Comparative approaches to genetic discrimination: chasing shadows? Trends Genet. 33, 299–302 (2017).
Yoshizawa, G. et al. ELSI practices in genomic research in East Asia: implications for research collaboration and public participation. Genome Med. 6, 39 (2014).
Joly, Y., Ngueng Feze, I. & Simard, J. Genetic discrimination and life insurance: a systematic review of the evidence. BMC Med. 11, 25 (2013).
Council of Europe. Recommendation of the Committee of Ministers to the member States on the processing of personal health-related data for insurance purposes, including data resulting from genetic tests. Quotidiano Sanita http://www.quotidianosanita.it/allegati/allegato2027308.pdf (2016).
Zlotogora, J. Genetics and genomic medicine in Israel. Mol. Genet. Genomics Med. 2, 85–94 (2014).
Association of British Insurers. Concordat and moratorium on genetics and insurance. ABI https://www.abi.org.uk/globalassets/sitecore/files/documents/publications/public/2014/genetics/concordat-and-moratorium-on-genetics-and-insurance.pdf (2014).
Canadian Life and Health Insurance Association. Industry code on genetics testing information for insurance underwriting. CLHIA http://www.clhia.ca/domino/html/clhia/clhia_lp4w_lnd_webstation.nsf/page/E79687482615DFA485257D5D00682400!OpenDocument (2017).
Hudson, K. L. & Pollitz, K. Undermining genetic privacy? Employee wellness programs and the law. N. Engl. J. Med. 377, 1–3 (2017).
Manolio, T. A. et al. Bedside back to bench: building bridges between basic and clinical genomic research. Cell 169, 6–12 (2017). This article highlights key priorities for integrating genomic research with clinical care and proposes collaborative efforts between researchers, clinicians, and patients to help address them.
Tzur, S. et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum. Genet. 128, 345–350 (2010).
McLean, N. O., Robinson, T. W. & Freedman, B. I. APOL1 gene kidney risk variants and cardiovascular disease: getting to the heart of the matter. Am. J. Kidney Dis. 70, 281–289 (2017).
Freedman, B. I. et al. Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease. Kidney Int. 82, 805–811 (2012).
Divers, J. et al. Gene–gene interactions in APOL1-associated nephropathy. Nephrol. Dial. Transplant. 29, 587–594 (2014).
Kopp, J. B. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J. Am. Soc. Nephrol. 22, 2129–2137 (2011).
Kasembeli, A. N. et al. APOL1 risk variants are strongly associated with HIV-associated nephropathy in black South Africans. J. Am. Soc. Nephrol. 26, 2882–2890 (2015).
Newell, K. A. et al. Integrating APOL1 gene variants into renal transplantation: considerations arising from the American Society of Transplantation Expert Conference. Am. J. Transplant. 17, 901–911 (2017).
Harewood, L. et al. Bilateral renal agenesis/hypoplasia/dysplasia (BRAHD): postmortem analysis of 45 cases with breakpoint mapping of two de novo translocations. PLoS ONE 5, e12375 (2010).
Mansouri, M. R. et al. Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation. Hum. Genet. 119, 162–168 (2006).
Holmberg, C. & Jalanko, H. Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation. Pediatr. Nephrol. 29, 2309–2317 (2014).
Patrakka, J. et al. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 73, 394–403 (2002).
Ashraf, S. et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J. Clin. Invest. 123, 5179–5189 (2013).
Heeringa, S. F. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J. Clin. Invest. 121, 2013–2024 (2011).
Kashtan, C. Alport syndrome and thin basement membrane nephropathy. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1207/ (2015).
Bekheirnia, M. R. et al. Genotype-phenotype correlation in X-linked Alport syndrome. J. Am. Soc. Nephrol. 21, 876–883 (2010).
Kidney Disease Improving Global Outcomes Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int. Suppl. 2, 139–274 (2012).
Mitchel, M. W. et al. 17q12 recurrent deletion syndrome. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK401562 (2016).
Bollee, G. et al. Adenine phosphoribosyltransferase deficiency. Clin. J. Am. Soc. Nephrol. 7, 1521–1527 (2012).
Runolfsdottir, H. L., Palsson, R., Agustsdottir, I. M., Indridason, O. S. & Edvardsson, V. O. Kidney disease in adenine phosphoribosyltransferase deficiency. Am. J. Kidney Dis. 67, 431–438 (2016).
Kirmani, S. & Young, W. F. Hereditary paraganglioma-pheochromocytoma syndromes. GeneReviews https://www.ncbi.nlm.nih.gov/pubmed/books/NBK1548 (2014).
Rednam, S. P. et al. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin. Cancer Res. 23, e68–e75 (2017).
Bali, D. S., Chen, Y. T., Austin, S. & Goldstein, J. L. Glycogen storage disease type I. GeneReviews https://www.ncbi.nlm.nih.gov/pubmed/books/NBK1312 (2016).
Froissart, R. et al. Glucose-6-phosphatase deficiency. Orphanet J. Rare Dis. 6, 27 (2011).
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.).
The authors declare no competing financial interests.
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.
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.
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.
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.
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.
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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