Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Next-generation sequencing for research and diagnostics in kidney disease

Nature Reviews Nephrology volume 10, pages 433–444 (2014)Cite this article

Subjects

Key Points

  • Next-generation sequencing has enabled increasingly accurate and cost-effective methods for mutation detection in patients with inherited kidney disorders

  • As renal ciliopathies and congenital anomalies of the kidney and urinary tract are highly heterogeneous disorders, high-throughput sequencing approaches are required for identification of causal genes in research and diagnostics

  • Challenges for implementation of next-generation sequencing in clinical practice include ethical considerations and accurate interpretation of genetic variants

  • National and international multidisciplinary collaborations involving nephrologists, geneticists, biologists and bioinformaticians are crucial to enable elucidation of the genetic backgrounds of inherited kidney diseases in the research and diagnostics settings

Abstract

The advent of next-generation sequencing technologies has enabled genetic nephrology research to move beyond single gene analysis to the simultaneous investigation of hundreds of genes and entire pathways. These new sequencing approaches have been used to identify and characterize causal factors that underlie inherited heterogeneous kidney diseases such as nephronophthisis and congenital anomalies of the kidney and urinary tract. In this Review, we describe the development of next-generation sequencing in basic and clinical research and discuss the implementation of this novel technology in routine patient management. Widespread use of targeted and nontargeted approaches for gene identification in clinical practice will require consistent phenotyping, appropriate disease modelling and collaborative efforts to combine and integrate data analyses. Next-generation sequencing is an exceptionally promising technique that has the potential to improve the management of patients with inherited kidney diseases. However, identifying the molecular mechanisms that lead to renal developmental disorders and ciliopathies is difficult. A major challenge in the near future will be how best to integrate data obtained using next-generation sequencing with personalized medicine, including use of high-throughput disease modelling as a tool to support the clinical diagnosis of kidney diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Kidney disease modelling.
Figure 2: Next-generation sequencing for the diagnosis of nephrogenetic disorders.

Similar content being viewed by others

References

  1. Mong Hiep, T. T. et al. Clinical characteristics and outcomes of children with stage 3–5 chronic kidney disease. Pediatr. Nephrol. 25, 935–940 (2010).

    Article  PubMed  Google Scholar 

  2. Greenbaum, L. A., Warady, B. A. & Furth, S. L. Current advances in chronic kidney disease in children: growth, cardiovascular, and neurocognitive risk factors. Semin. Nephrol. 29, 425–434 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hildebrandt, F. Genetic kidney diseases. Lancet 375, 1287–1295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Neveling, K. et al. A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum. Mutat. 34, 1721–1726 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Pei, Y. & Watnick, T. Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv. Chronic Kidney Dis. 17, 140–152 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tory, K. et al. High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J. Am. Soc. Nephrol. 18, 1566–1575 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Hoefele, J. et al. Evidence of oligogenic inheritance in nephronophthisis. J. Am. Soc. Nephrol. 18, 2789–2795 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Sanger, F. & Coulson, A. R. A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J. Mol. Biol. 94, 441–448 (1975).

    Article  CAS  PubMed  Google Scholar 

  9. Sanger, F., Nicklen, S. & Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomas, R. et al. Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR. Am. J. Hum. Genet. 65, 39–49 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Hehir-Kwa, J. Y., Pfundt, R., Veltman, J. A. & de Leeuw, N. Pathogenic or not? Assessing the clinical relevance of copy number variants. Clin. Genet. 84, 415–421 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Drmanac, R. The advent of personal genome sequencing. Genet. Med. 13, 188–190 (2011).

    Article  PubMed  Google Scholar 

  14. Need, A. C. et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49, 353–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Yang, Y. et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 369, 1502–1511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gilissen, C., Hoischen, A., Brunner, H. G. & Veltman, J. A. Unlocking Mendelian disease using exome sequencing. Genome Biol. 12, 228 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Otto, E. A. et al. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat. Genet. 42, 840–850 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lovric, S. et al. Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. http://dx.doi.org/10.2215/CJN.09010813.

  19. Nijman, I. J. et al. Mutation discovery by targeted genomic enrichment of multiplexed barcoded samples. Nat. Methods 7, 913–915 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Cummings, N. et al. Combining target enrichment with barcode multiplexing for high throughput SNP discovery. BMC Genomics 11, 641 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Harakalova, M. et al. Multiplexed array-based and in-solution genomic enrichment for flexible and cost-effective targeted next-generation sequencing. Nat. Protoc. 6, 1870–1886 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Teer, J. K. et al. Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res. 20, 1420–1431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Turner, E. H., Ng, S. B., Nickerson, D. A. & Shendure, J. Methods for genomic partitioning. Annu. Rev. Genomics Hum. Genet. 10, 263–284 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Frank, M., Prenzler, A., Eils, R. & Graf von der Schulenburg, J. M. Genome sequencing: a systematic review of health economic evidence. Health Econ. Rev. 3, 29 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fuchs, S. A. et al. Application of exome sequencing in the search for genetic causes of rare disorders of copper metabolism. Metallomics 4, 606–613 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, X. Exome sequencing greatly expedites the progressive research of Mendelian diseases. Front. Med. 8, 42–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. International HapMap 3 Consortium et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).

  29. Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Jouan, L., Gauthier, J., Dion, P. A. & Rouleau, G. A. Rare variants in complex traits: novel identification strategies and the role of de novo mutations. Hum. Hered. 74, 215–225 (2012).

    Article  PubMed  Google Scholar 

  31. Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Vissers, L. E. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S. & Goldstein, D. B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. NHLBI Exome Sequencing Project. Exome Variant Server. evs.gs.washington.edu [online], (2014).

  37. Dorschner, M. O. et al. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am. J. Hum. Genet. 93, 631–640 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Abdul-Karim, R. et al. Disclosure of incidental findings from next-generation sequencing in pediatric genomic research. Pediatrics 131, 564–571 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Christenhusz, G. M., Devriendt, K. & Dierickx, K. To tell or not to tell? A systematic review of ethical reflections on incidental findings arising in genetics contexts. Eur. J. Hum. Genet. 21, 248–255 (2013).

    Article  PubMed  Google Scholar 

  40. Lolkema, M. P. et al. Ethical, legal, and counseling challenges surrounding the return of genetic results in oncology. J. Clin. Oncol. 31, 1842–1848 (2013).

    Article  PubMed  Google Scholar 

  41. Bredenoord, A. L., Kroes, H. Y., Cuppen, E., Parker, M. & van Delden, J. J. Disclosure of individual genetic data to research participants: the debate reconsidered. Trends Genet. 27, 41–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tan, A. Y. et al. molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J. Mol. Diagn. 16, 216–228 (2013).

    Article  PubMed  CAS  Google Scholar 

  44. Below, J. E. et al. Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. Am. J. Hum. Genet. 92, 137–143 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hildebrandt, F. et al. A systematic approach to mapping recessive disease genes in individuals from outbred populations. PLoS Genet. 5, e1000353 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Katsanis, S. H. & Katsanis, N. Molecular genetic testing and the future of clinical genomics. Nat. Rev. Genet. 14, 415–426 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364, 1533–1543 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Eggenschwiler, J. T. & Anderson, K. V. Cilia and developmental signaling. Annu. Rev. Cell Dev. Biol. 23, 345–373 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barr, M. M. & Sternberg, P. W. A polycystic kidney-disease gene homologue required for male mating behaviour in, C. elegans. Nature 401, 386–389 (1999).

    CAS  PubMed  Google Scholar 

  51. The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77, 881–894 (1994).

    Article  Google Scholar 

  52. Gunay-Aygun, M. Liver and kidney disease in ciliopathies. Am. J. Med. Genet. C Semin. Med. Genet. 151C, 296–306 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hurd, T. W. & Hildebrandt, F. Mechanisms of nephronophthisis and related ciliopathies. Nephron Exp. Nephrol. 118, e9–e14 (2011).

    Article  PubMed  Google Scholar 

  54. Hildebrandt, F., Attanasio, M. & Otto, E. Nephronophthisis: disease mechanisms of a ciliopathy. J. Am. Soc. Nephrol. 20, 23–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Gagnadoux, M. F., Bacri, J. L., Broyer, M. & Habib, R. Infantile chronic tubulo-interstitial nephritis with cortical microcysts: variant of nephronophthisis or new disease entity? Pediatr. Nephrol. 3, 50–55 (1989).

    Article  CAS  PubMed  Google Scholar 

  56. Blowey, D. L., Querfeld, U., Geary, D., Warady, B. A. & Alon, U. Ultrasound findings in juvenile nephronophthisis. Pediatr. Nephrol. 10, 22–24 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Chung, E. M., Conran, R. M., Schroeder, J. W., Rohena-Quinquilla, I. R. & Rooks, V. J. From the radiologic pathology archives: pediatric polycystic kidney disease and other ciliopathies: radiologic-pathologic correlation. Radiographics 34, 155–178 (2014).

    Article  PubMed  Google Scholar 

  58. Waldherr, R., Lennert, T., Weber, H. P., Fodisch, H. J. & Scharer, K. The nephronophthisis complex. A clinicopathologic study in children. Virchows Arch. A Pathol. Anat. Histol. 394, 235–254 (1982).

    Article  CAS  PubMed  Google Scholar 

  59. Soliman, N. A. et al. Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience. Saudi J. Kidney Dis. Transpl. 23, 1090–1098 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hoff, S. et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat. Genet. 45, 951–956 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Simms, R. J., Hynes, A. M., Eley, L. & Sayer, J. A. Nephronophthisis: a genetically diverse ciliopathy. Int. J. Nephrol. 2011, 527137 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Arts, H. H. & Knoers, N. V. Current insights into renal ciliopathies: what can genetics teach us? Pediatr. Nephrol. 28, 863–874 (2013).

    Article  PubMed  Google Scholar 

  63. Attanasio, M. et al. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat. Genet. 39, 1018–1024 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Otto, E. A. et al. Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy. J. Med. Genet. 48, 105–116 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Yuan, S. & Sun, Z. Expanding horizons: ciliary proteins reach beyond cilia. Annu. Rev. Genet. 47, 353–376 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Gee, H. Y. et al. Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int. (2013).

  69. Bredrup, C. et al. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am. J. Hum. Genet. 89, 634–643 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chaki, M. et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150, 533–548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, J. H. et al. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science 335, 966–969 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Edvardson, S. et al. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am. J. Hum. Genet. 86, 93–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nasonkin, I. O. et al. Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis. Development 140, 1330–1341 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Nishiguchi, K. M. et al. Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc. Natl Acad. Sci. USA 110, 16139–16144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Loane, M. et al. Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe. Birth Defects Res. A Clin. Mol. Teratol. 91 (Suppl. 1), S31–S43 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Melo, B. F. et al. Early risk factors for neonatal mortality in CAKUT: analysis of 524 affected newborns. Pediatr. Nephrol. 27, 965–972 (2012).

    Article  PubMed  Google Scholar 

  77. Groothoff, J. W. et al. Social consequences in adult life of end-stage renal disease in childhood. J. Pediatr. 146, 512–517 (2005).

    Article  PubMed  Google Scholar 

  78. European Renal Association–European dialysis and Transplant Association. ERA–EDTA Registry Annual Report 2011. era-edta-reg.org [online], (2011).

  79. Madariaga, L. et al. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin. J. Am. Soc. Nephrol. 8, 1179–1187 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Belk, R. A. et al. A family study and the natural history of prenatally detected unilateral multicystic dysplastic kidney. J. Urol. 167, 666–669 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Bulum, B. et al. High frequency of kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. Pediatr. Nephrol. 28, 2143–2147 (2013).

    Article  PubMed  Google Scholar 

  82. Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Winyard, P. & Chitty, L. S. Dysplastic kidneys. Semin. Fetal Neonatal Med. 13, 142–151 (2008).

    Article  PubMed  Google Scholar 

  84. Little, M., Georgas, K., Pennisi, D. & Wilkinson, L. Kidney development: two tales of tubulogenesis. Curr. Top. Dev. Biol. 90, 193–229 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Schedl, A. Renal abnormalities and their developmental origin. Nat. Rev. Genet. 8, 791–802 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. 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. http://dx.doi.org/10.1038/ki.2013.508.

  87. Humbert, C. et al. Integrin α8 recessive mutations are responsible for bilateral renal agenesis in humans. Am. J. Hum. Genet. 94, 288–294 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Naseri, M., Ghiggeri, G. M., Caridi, G. & Abbaszadegan, M. R. Five cases of severe vesico-ureteric reflux in a family with an X-linked compatible trait. Pediatr. Nephrol. 25, 349–352 (2010).

    Article  PubMed  Google Scholar 

  89. Kerecuk, L. et al. Autosomal dominant inheritance of non-syndromic renal hypoplasia and dysplasia: dramatic variation in clinical severity in a single kindred. Nephrol. Dial. Transplant. 22, 259–263 (2007).

    Article  PubMed  Google Scholar 

  90. Fletcher, J., McDonald, S., Alexander, S. I. & Australian & New Zealand Pediatric Nephrology Association. Prevalence of genetic renal disease in children. Pediatr. Nephrol. 28, 251–256 (2013).

    Article  PubMed  Google Scholar 

  91. Renkema, K. Y. et al. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT). Nephrol. Dial. Transplant. 26, 3843–3851 (2011).

    Article  PubMed  Google Scholar 

  92. Sanna-Cherchi, S. et al. Copy-number disorders are a common cause of congenital kidney malformations. Am. J. Hum. Genet. 91, 987–997 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gbadegesin, R. A. et al. TNXB mutations can cause vesicoureteral reflux. J. Am. Soc. Nephrol. 24, 1313–1322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Saisawat, P. et al. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int. http://dx.doi.org/10.1038/ki.2013.417.

  95. Sanna-Cherchi, S. et al. Mutations in DSTYK and dominant urinary tract malformations. N. Engl. J. Med. 369, 621–629 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Vivante, A. et al. Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling. J. Am. Soc. Nephrol. 24, 550–558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Djuric, T. et al. MMP-1 and -3 haplotype is associated with congenital anomalies of the kidney and urinary tract. Pediatr. Nephrol. 29, 879–884 (2014).

    Article  PubMed  Google Scholar 

  98. Barak, H. et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22, 1191–1207 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kaku, Y. et al. Islet1 deletion causes kidney agenesis and hydroureter resembling CAKUT. J. Am. Soc. Nephrol. 24, 1242–1249 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Saisawat, P. et al. Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int. 81, 196–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. de Groot, T. et al. Lithium causes G2 arrest of renal principal cells. J. Am. Soc. Nephrol. 25, 501–510 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sang, L. et al. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145, 513–528 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Choi, H. J. et al. NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies. Mol. Cell 51, 423–439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Luijten, M. N. et al. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum. Mol. Genet. 22, 4383–4397 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ebarasi, L., Oddsson, A., Hultenby, K., Betsholtz, C. & Tryggvason, K. Zebrafish: a model system for the study of vertebrate renal development, function, and pathophysiology. Curr. Opin. Nephrol. Hypertens. 20, 416–424 (2011).

    Article  PubMed  Google Scholar 

  106. Kaufman, C. K., White, R. M. & Zon, L. Chemical genetic screening in the zebrafish embryo. Nat. Protoc. 4, 1422–1432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Basten, S. G. et al. Mutations in LRRC50 predispose zebrafish and humans to seminomas. PLoS Genet. 9, e1003384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ross, A. J. et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat. Genet. 37, 1135–1140 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Zaghloul, N. A. & Katsanis, N. Zebrafish assays of ciliopathies. Methods Cell Biol. 105, 257–272 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Feeney, M. M. & Rosenblum, N. D. Urinary tract pacemaker cells: current knowledge and insights from nonrenal pacemaker cells provide a basis for future discovery. Pediatr. Nephrol. 4, 629–635 (2013).

    Google Scholar 

  111. Burn, S. F. et al. Calcium/NFAT signalling promotes early nephrogenesis. Dev. Biol. 352, 288–298 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Davies, J. A. et al. Development of an siRNA-based method for repressing specific genes in renal organ culture and its use to show that the Wt1 tumour suppressor is required for nephron differentiation. Hum. Mol. Genet. 13, 235–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Barker, N. et al. Lgr5+ve stem/progenitor cells contribute to nephron formation during kidney development. Cell Rep. 2, 540–552 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Inoue, H., Nagata, N., Kurokawa, H. & Yamanaka, S. iPS cells: a game changer for future medicine. EMBO J. 33, 409–417 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Meir, Y. J. et al. A versatile, highly efficient, and potentially safer piggyBac transposon system for mammalian genome manipulations. FASEB J. 27, 4429–4443 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Hockemeyer, D. et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat. Biotechnol. 29, 731–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lam, A. Q. et al. Rapid and efficient differentiation of human pluripotent stem cells into intermediate mesoderm that forms tubules expressing kidney proximal tubular markers. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2013080831.

  119. Takasato, M. et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16, 118–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Coene, K. L. et al. The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Hum. Mol. Genet. 20, 3592–3605 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Boldt, K. et al. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. J. Clin. Invest. 121, 2169–2180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mimura, I., Kanki, Y., Kodama, T. & Nangaku, M. Revolution of nephrology research by deep sequencing: ChIP-seq and RNA-seq. Kidney Int. 85, 31–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. European project SYSCILIA. Syscilia [online], (2014).

  124. van Dam, T. J. et al. The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium. Cilia 2, 7 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ku, C. S. et al. Exome sequencing: dual role as a discovery and diagnostic tool. Ann. Neurol. 71, 5–14 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Robinson, P. N. et al. The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 83, 610–615 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. The Human Phenotype Ontology Project. Human Phenotype Ontology Website [online], (2014).

  128. Gattone, V. H. 2nd, Wang, X., Harris, P. C. & Torres, V. E. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9, 1323–1326 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Sayer, J. A. et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat. Genet. 38, 674–681 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Torres, V. E. et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 10, 363–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Shillingford, J. M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl Acad. Sci. USA 103, 5466–5471 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, S. & Dong, Z. Primary cilia and kidney injury: current research status and future perspectives. Am. J. Physiol. Renal Physiol. 305, F1085–F1098 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tobin, J. L. & Beales, P. L. Restoration of renal function in zebrafish models of ciliopathies. Pediatr. Nephrol. 23, 2095–2099 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Cao, Y. et al. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc. Natl Acad. Sci. USA 106, 21819–21824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chamling, X. et al. Ectopic expression of human BBS4 can rescue Bardet-Biedl syndrome phenotypes in Bbs4 null mice. PLoS ONE 8, e59101 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. McCampbell, K. K. & Wingert, R. A. New tides: using zebrafish to study renal regeneration. Transl. Res. 163, 109–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Genin, E., Feingold, J. & Clerget-Darpoux, F. Identifying modifier genes of monogenic disease: strategies and difficulties. Hum. Genet. 124, 357–368 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Iatropoulos, P. et al. Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation. Pediatr. Nephrol. 27, 1989–1993 (2012).

    Article  PubMed  Google Scholar 

  139. Zhang, Y. et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum. Mol. Genet. 23, 40–51 (2014).

    Article  PubMed  CAS  Google Scholar 

  140. European Consortium for High-throughput Research in Rare Kidney Diseases. EURenOmics [online], (2014).

  141. Bartlett, Y. K. & Coulson, N. S. An investigation into the empowerment effects of using online support groups and how this affects health professional/patient communication. Patient Educ. Couns. 83, 113–119 (2011).

    Article  PubMed  Google Scholar 

  142. Saunier, S. et al. A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis. Hum. Mol. Genet. 6, 2317–2323 (1997).

    Article  CAS  PubMed  Google Scholar 

  143. Hildebrandt, F. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat. Genet. 17, 149–153 (1997).

    Article  CAS  PubMed  Google Scholar 

  144. Otto, E. A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat. Genet. 34, 413–420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Olbrich, H. et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat. Genet. 34, 455–459 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Mollet, G. et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat. Genet. 32, 300–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Otto, E. et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am. J. Hum. Genet. 71, 1161–1167 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Otto, E. A. et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat. Genet. 37, 282–288 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Delous, M. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat. Genet. 39, 875–881 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Otto, E. A. et al. NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. J. Am. Soc. Nephrol. 19, 587–592 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Davis, E. E. et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat. Genet. 43, 189–196 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Halbritter, J. et al. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am. J. Hum. Genet. 93, 915–925 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' research was supported by grants from the European Community's Seventh Framework Programme FP7/2009 under grant agreements 305608 (EURenOmics) and 241955 (SYSCILIA) and the Consortium Programme of the Dutch Kidney Foundation under grant agreement CP11.18 (KOUNCIL).

Author information

Authors and Affiliations

  1. Department of Medical Genetics, University Medical Center Utrecht, KC04.048.02, PO Box 85090, Utrecht, 3508, AB, Netherlands

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

  2. Department of Nephrology and Hypertension, University Medical Center Utrecht, KC04.048.02, PO Box 85090, Utrecht, 3508, AB, Netherlands

    Rachel H. Giles

Authors
  1. Kirsten Y. Renkema
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marijn F. Stokman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel H. Giles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nine V. A. M. Knoers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data, wrote the article, made a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Nine V. A. M. Knoers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Renkema, K., Stokman, M., Giles, R. et al. Next-generation sequencing for research and diagnostics in kidney disease. Nat Rev Nephrol 10, 433–444 (2014). https://doi.org/10.1038/nrneph.2014.95

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2014.95

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing