Skip to main content

Advertisement

SpringerLink
Log in

Towards precision nephrology: the opportunities and challenges of genomic medicine

  • Review
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

The expansion of genomic medicine is furthering our understanding of many human diseases. This is well illustrated in the field of nephrology, through the characterization, discovery, and growing insight into various renal diseases through use of Next Generation Sequencing (NGS) technologies. This review will provide an overview of the diagnostic opportunities of using genetic testing in the clinical setting by describing notable discoveries regarding inherited forms of renal disease that have advanced the field and by highlighting some of the potential benefits of establishing a molecular diagnosis in a clinical practice. In addition, it will discuss some of the challenges associated with the expansion of genetic testing into the clinical setting, including clinical variant interpretation and return of genetic results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vivante A, Hildebrandt F (2016) Exploring the genetic basis of early-onset chronic kidney disease. Nat Rev Nephrol 12(3):133–146. doi:10.1038/nrneph.2015.205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Santin S, Bullich G, Tazon-Vega B, Garcia-Maset R, Gimenez I, Silva I, Ruiz P, Ballarin J, Torra R, Ars E (2011) Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clinical journal of the American Society of Nephrology : CJASN 6(5):1139–1148. doi:10.2215/cjn.05260610

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mallett AJ, McCarthy HJ, Ho G, Holman K, Farnsworth E, Patel C, Fletcher JT, Mallawaarachchi A, Quinlan C, Bennetts B, Alexander SI (2017) Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders. Kidney international. doi:10.1016/j.kint.2017.06.013

    PubMed  Google Scholar 

  4. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). Accessed at: https://omim.org/

  5. http://www.who.int/genomics/public/geneticdiseases. Accessed 11 July 2017

  6. Baird PA, Anderson TW, Newcombe HB, Lowry RB (1988) Genetic disorders in children and young adults: a population study. Am J Hum Genet 42(5):677–693

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shashi V, McConkie-Rosell A, Rosell B, Schoch K, Vellore K, McDonald M, Jiang YH, Xie P, Need A, Goldstein DB (2014) The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med 16(2):176–182. doi:10.1038/gim.2013.99

    Article  CAS  PubMed  Google Scholar 

  8. Gilissen C, Hoischen A, Brunner HG, Veltman JA (2012) Disease gene identification strategies for exome sequencing. Eur J Hum Genet 20(5):490–497. doi:10.1038/ejhg.2011.258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Benn P, Borrell A, Chiu RW, Cuckle H, Dugoff L, Faas B, Gross S, Huang T, Johnson J, Maymon R, Norton M, Odibo A, Schielen P, Spencer K, Wright D, Yaron Y (2015) Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 35(8):725–734. doi:10.1002/pd.4608

    Article  PubMed  Google Scholar 

  10. Dancey JE, Bedard PL, Onetto N, Hudson TJ (2012) The genetic basis for cancer treatment decisions. Cell 148(3):409–420. doi:10.1016/j.cell.2012.01.014

    Article  CAS  PubMed  Google Scholar 

  11. Kurian AW, Hare EE, Mills MA, Kingham KE, McPherson L, Whittemore AS, McGuire V, Ladabaum U, Kobayashi Y, Lincoln SE, Cargill M, Ford JM (2014) Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32(19):2001–2009. doi:10.1200/jco.2013.53.6607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Foulkes WD, Knoppers BM, Turnbull C (2016) Population genetic testing for cancer susceptibility: founder mutations to genomes. Nat Rev Clin Oncol 13(1):41–54. doi:10.1038/nrclinonc.2015.173

    Article  CAS  PubMed  Google Scholar 

  13. Mardis ER (2011) A decade’s perspective on DNA sequencing technology. Nature 470(7333):198–203. doi:10.1038/nature09796

    Article  CAS  PubMed  Google Scholar 

  14. Xue Y, Ankala A, Wilcox WR, Hegde MR (2015) 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(6):444–451. doi:10.1038/gim.2014.122

    Article  CAS  PubMed  Google Scholar 

  15. Metzker ML (2010) Sequencing technologies - the next generation. Nat Rev Genet 11(1):31–46. doi:10.1038/nrg2626

    Article  CAS  PubMed  Google Scholar 

  16. Directors ABo (2012) Points to consider in the clinical application of genomic sequencing. Genet Med 14(8):759–761. doi:10.1038/gim.2012.74

    Article  Google Scholar 

  17. Klee EW, Hoppman-Chaney NL, Ferber MJ (2011) Expanding DNA diagnostic panel testing: is more better? Expert Rev Mol Diagn 11(7):703–709. doi:10.1586/erm.11.58

    Article  CAS  PubMed  Google Scholar 

  18. Rabbani B, Mahdieh N, Hosomichi K, Nakaoka H, Inoue I (2012) Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders. Journal of human genetics 57(10):621–632. doi:10.1038/jhg.2012.91

    Article  CAS  PubMed  Google Scholar 

  19. Zawati MH, Parry D, Thorogood A, Nguyen MT, Boycott KM, Rosenblatt D, Knoppers BM (2014) Reporting results from whole-genome and whole-exome sequencing in clinical practice: a proposal for Canada? Journal of medical genetics 51(1):68–70. doi:10.1136/jmedgenet-2013-101934

    Article  PubMed  Google Scholar 

  20. Sawyer SL, Hartley T, Dyment DA, Beaulieu CL, Schwartzentruber J, Smith A, Bedford HM, Bernard G, Bernier FP, Brais B, Bulman DE, Warman Chardon J, Chitayat D, Deladoey J, Fernandez BA, Frosk P, Geraghty MT, Gerull B, Gibson W, Gow RM, Graham GE, Green JS, Heon E, Horvath G, Innes AM, Jabado N, Kim RH, Koenekoop RK, Khan A, Lehmann OJ, Mendoza-Londono R, Michaud JL, Nikkel SM, Penney LS, Polychronakos C, Richer J, Rouleau GA, Samuels ME, Siu VM, Suchowersky O, Tarnopolsky MA, Yoon G, Zahir FR, Majewski J, Boycott KM (2016) Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet 89(3):275–284. doi:10.1111/cge.12654

    Article  CAS  PubMed  Google Scholar 

  21. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE (2012) Diagnostic exome sequencing in persons with severe intellectual disability. The New England journal of medicine 367(20):1921–1929. doi:10.1056/NEJMoa1206524

    Article  PubMed  CAS  Google Scholar 

  22. Shen T, Pajaro-Van de Stadt SH, Yeat NC, Lin JC (2015) Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes. Front Genet 6:215. doi:10.3389/fgene.2015.00215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. The New England journal of medicine 369(16):1502–1511. doi:10.1056/NEJMoa1306555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. Jama 312(18):1880–1887. doi:10.1001/jama.2014.14604

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M, Patel A, Boerwinkle E, Beaudet AL, Lupski JR, Plon SE, Gibbs RA, Eng CM (2014) Molecular findings among patients referred for clinical whole-exome sequencing. Jama 312(18):1870–1879. doi:10.1001/jama.2014.14601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, Ben-Zeev B, Nissenkorn A, Anikster Y, Oz-Levi D, Dhindsa RS, Hitomi Y, Schoch K, Spillmann RC, Heimer G, Marek-Yagel D, Tzadok M, Han Y, Worley G, Goldstein J, Jiang YH, Lancet D, Pras E, Shashi V, McHale D, Need AC, Goldstein DB (2015) Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med 17(10):774–781. doi:10.1038/gim.2014.191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, McKnight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Brandt T, Haverfield E, Chung WK, Bale S (2016) Clinical application of whole-exome sequencing across clinical indications. Genet Med 18(7):696–704. doi:10.1038/gim.2015.148

    Article  CAS  PubMed  Google Scholar 

  28. Neveling K, Feenstra I, Gilissen C, Hoefsloot LH, Kamsteeg EJ, Mensenkamp AR, Rodenburg RJ, Yntema HG, Spruijt L, Vermeer S, Rinne T, van Gassen KL, Bodmer D, Lugtenberg D, de Reuver R, Buijsman W, Derks RC, Wieskamp N, van den Heuvel B, Ligtenberg MJ, Kremer H, Koolen DA, van de Warrenburg BP, Cremers FP, Marcelis CL, Smeitink JA, Wortmann SB, van Zelst-Stams WA, Veltman JA, Brunner HG, Scheffer H, Nelen MR (2013) A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat 34(12):1721–1726. doi:10.1002/humu.22450

    Article  CAS  PubMed  Google Scholar 

  29. Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, Merker JD, Goldfeder RL, Enns GM, David SP, Pakdaman N, Ormond KE, Caleshu C, Kingham K, Klein TE, Whirl-Carrillo M, Sakamoto K, Wheeler MT, Butte AJ, Ford JM, Boxer L, Ioannidis JP, Yeung AC, Altman RB, Assimes TL, Snyder M, Ashley EA, Quertermous T (2014) Clinical interpretation and implications of whole-genome sequencing. Jama 311(10):1035–1045. doi:10.1001/jama.2014.1717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511(7509):344–347. doi:10.1038/nature13394

    Article  CAS  PubMed  Google Scholar 

  31. Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Nemeth AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sorensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G (2015) Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nature genetics 47(7):717–726. doi:10.1038/ng.3304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Foley SB, Rios JJ, Mgbemena VE, Robinson LS, Hampel HL, Toland AE, Durham L, Ross TS (2015) Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. EBioMedicine 2. (1):74–81. doi:10.1016/j.ebiom.2014.12.003

  33. Strande NT, Berg JS (2016) Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing. Annu Rev Genomics Hum Genet 17:303–332. doi:10.1146/annurev-genom-083115-022348

    Article  CAS  PubMed  Google Scholar 

  34. Prakash S, Gharavi AG (2015) Diagnosing kidney disease in the genetic era. Curr Opin Nephrol Hypertens 24(4):380–387. doi:10.1097/mnh.0000000000000139

    PubMed  Google Scholar 

  35. Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F (2013) Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. Journal of the American Society of Nephrology : JASN 24(3):364–375. doi:10.1681/asn.2012020148

    Article  CAS  PubMed  Google Scholar 

  36. Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, Bole-Feysot C, Pruvost S, Nitschke P, Plaisier E, Knebelmann B, Macher MA, Noel LH, Gubler MC, Antignac C, Heidet L (2014) Improving mutation screening in familial hematuric nephropathies through next generation sequencing. Journal of the American Society of Nephrology : JASN 25(12):2740–2751. doi:10.1681/asn.2013080912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sampson MG, Gillies CE, Robertson CC, Crawford B, Vega-Warner V, Otto EA, Kretzler M, Kang HM (2016) Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort. Journal of the American Society of Nephrology : JASN 27(7):1970–1983. doi:10.1681/asn.2015050504

    Article  CAS  PubMed  Google Scholar 

  38. Lovric S, Ashraf S, Tan W, Hildebrandt F (2016) Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -. European Renal Association 31(11):1802–1813. doi:10.1093/ndt/gfv355

    CAS  Google Scholar 

  39. Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. Journal of the American Society of Nephrology : JASN 26(6):1279–1289. doi:10.1681/asn.2014050489

    Article  CAS  PubMed  Google Scholar 

  40. Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E, Ding WY, Nabhan MM, Kerecuk L, Hegde S, Hughes D, Marks S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M, Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB, Welsh GI, Saleem MA (2017) Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney international. doi:10.1016/j.kint.2016.10.013

    PubMed  Google Scholar 

  41. Maas RJ, Deegens JK, Smeets B, Moeller MJ, Wetzels JF (2016) Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol 12(12):768–776. doi:10.1038/nrneph.2016.147

    Article  PubMed  Google Scholar 

  42. Becherucci F, Mazzinghi B, Provenzano A, Murer L, Giglio S, Romagnani P (2016) Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome? Journal of nephrology 29(4):543–550. doi:10.1007/s40620-016-0315-4

    Article  CAS  PubMed  Google Scholar 

  43. Arts HH, Knoers NV (2013) Current insights into renal ciliopathies: what can genetics teach us? Pediatric nephrology (Berlin, Germany) 28. (6):863–874. doi:10.1007/s00467-012-2259-9

  44. Oud MM, Lamers IJ, Arts HH (2017) Ciliopathies: Genetics in Pediatric Medicine. J Pediatr Genet 6(1):18–29. doi:10.1055/s-0036-1593841

    Article  CAS  PubMed  Google Scholar 

  45. Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S, Ghosh AK, Murga-Zamalloa CA, van Reeuwijk J, Letteboer SJ, Sang L, Giles RH, Liu Q, Coene KL, Estrada-Cuzcano A, Collin RW, McLaughlin HM, Held S, Kasanuki JM, Ramaswami G, Conte J, Lopez I, Washburn J, Macdonald J, Hu J, Yamashita Y, Maher ER, Guay-Woodford LM, Neumann HP, Obermuller N, Koenekoop RK, Bergmann C, Bei X, Lewis RA, Katsanis N, Lopes V, Williams DS, Lyons RH, Dang CV, Brito DA, Dias MB, Zhang X, Cavalcoli JD, Nurnberg G, Nurnberg P, Pierce EA, Jackson PK, Antignac C, Saunier S, Roepman R, Dollfus H, Khanna H, Hildebrandt F (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature genetics 42(10):840–850. doi:10.1038/ng.662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kang HG, Lee HK, Ahn YH, Joung JG, Nam J, Kim NK, Ko JM, Cho MH, Shin JI, Kim J, Park HW, Park YS, Ha IS, Chung WY, Lee DY, Kim SY, Park WY, Cheong HI (2016) Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. Exp Mol Med 48:e251. doi:10.1038/emm.2016.63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Halbritter J, Diaz K, Chaki M, Porath JD, Tarrier B, Fu C, Innis JL, Allen SJ, Lyons RH, Stefanidis CJ, Omran H, Soliman NA, Otto EA (2012) High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing. Journal of medical genetics 49(12):756–767. doi:10.1136/jmedgenet-2012-100973

    Article  CAS  PubMed  Google Scholar 

  48. Saisawat P, Kohl S, Hilger AC, Hwang DY, Yung Gee H, Dworschak GC, Tasic V, Pennimpede T, Natarajan S, Sperry E, Matassa DS, Stajic N, Bogdanovic R, de Blaauw I, Marcelis CL, Wijers CH, Bartels E, Schmiedeke E, Schmidt D, Marzheuser S, Grasshoff-Derr S, Holland-Cunz S, Ludwig M, Nothen MM, Draaken M, Brosens E, Heij H, Tibboel D, Herrmann BG, Solomon BD, de Klein A, van Rooij IA, Esposito F, Reutter HM, Hildebrandt F (2014) Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney international 85(6):1310–1317. doi:10.1038/ki.2013.417

    Article  CAS  PubMed  Google Scholar 

  49. Humbert C, Silbermann F, Morar B, Parisot M, Zarhrate M, Masson C, Tores F, Blanchet P, Perez MJ, Petrov Y, Khau Van Kien P, Roume J, Leroy B, Gribouval O, Kalaydjieva L, Heidet L, Salomon R, Antignac C, Benmerah A, Saunier S, Jeanpierre C (2014) Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am J Hum Genet 94(2):288–294. doi:10.1016/j.ajhg.2013.12.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bekheirnia MR, Bekheirnia N, Bainbridge MN, Gu S, Coban Akdemir ZH, Gambin T, Janzen NK, Jhangiani SN, Muzny DM, Michael M, Brewer ED, Elenberg E, Kale AS, Riley AA, Swartz SJ, Scott DA, Yang Y, Srivaths PR, Wenderfer SE, Bodurtha J, Applegate CD, Velinov M, Myers A, Borovik L, Craigen WJ, Hanchard NA, Rosenfeld JA, Lewis RA, Gonzales ET, Gibbs RA, Belmont JW, Roth DR, Eng C, Braun MC, Lupski JR, Lamb DJ (2016) 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. doi:10.1038/gim.2016.131

    PubMed  PubMed Central  Google Scholar 

  51. Vivante A, Hwang DY, Kohl S, Chen J, Shril S, Schulz J, van der Ven A, Daouk G, Soliman NA, Kumar AS, Senguttuvan P, Kehinde EO, Tasic V, Hildebrandt F (2017) Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract. Journal of the American Society of Nephrology : JASN 28(1):69–75. doi:10.1681/asn.2015080962

    Article  PubMed  Google Scholar 

  52. Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F (2014) Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney international 85(6):1429–1433. doi:10.1038/ki.2013.508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I, Burchette J, Wu G, Homstad A, Sparks MA, Gomez J, Jiang R, Alonso A, Lavin P, Conlon P, Korstanje R, Stander MC, Shamsan G, Barua M, Spurney R, Singhal PC, Kopp JB, Haller H, Howell D, Pollak MR, Shaw AS, Schiffer M, Winn MP (2014) Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. Journal of the American Society of Nephrology : JASN 25(9):1991–2002. doi:10.1681/asn.2013090976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xie J, Hao X, Azeloglu EU, Ren H, Wang Z, Ma J, Liu J, Ma X, Wang W, Pan X, Zhang W, Zhong F, Li Y, Meng G, Kiryluk K, He JC, Gharavi AG, Chen N (2015) Novel mutations in the inverted formin 2 gene of Chinese families contribute to focal segmental glomerulosclerosis. Kidney international 88(3):593–604. doi:10.1038/ki.2015.106

    Article  CAS  PubMed  Google Scholar 

  55. Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature genetics 45(5):531–536. doi:10.1038/ng.2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang C, Chen P, Lu D, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M (2013) DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. Journal of the American Society of Nephrology : JASN 24(3):377–384. doi:10.1681/asn.2012090903

    Article  CAS  PubMed  Google Scholar 

  57. Sanchez Chinchilla D, Pinto S, Hoppe B, Adragna M, Lopez L, Justa Roldan ML, Pena A, Lopez Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2014) Complement mutations in diacylglycerol kinase-epsilon-associated atypical hemolytic uremic syndrome. Clinical journal of the American Society of Nephrology : CJASN 9(9):1611–1619. doi:10.2215/cjn.01640214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Bruneau S, Neel M, Roumenina LT, Frimat M, Laurent L, Fremeaux-Bacchi V, Fakhouri F (2015) Loss of DGKepsilon induces endothelial cell activation and death independently of complement activation. Blood 125(6):1038–1046. doi:10.1182/blood-2014-06-579953

    Article  CAS  PubMed  Google Scholar 

  59. Mele C, Lemaire M, Iatropoulos P, Piras R, Bresin E, Bettoni S, Bick D, Helbling D, Veith R, Valoti E, Donadelli R, Murer L, Neunhauserer M, Breno M, Fremeaux-Bacchi V, Lifton R, Remuzzi G, Noris M (2015) Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome. Clinical journal of the American Society of Nephrology : CJASN 10(6):1011–1019. doi:10.2215/cjn.08520814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ma R, Deng L, Xia Y, Wei X, Cao Y, Guo R, Zhang R, Guo J, Liang D, Wu L (2017) A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies. Scientific reports 7:44446. doi:10.1038/srep44446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lee C, Scherer SW (2010) The clinical context of copy number variation in the human genome. Expert Rev Mol Med 12:e8. doi:10.1017/s1462399410001390

    Article  PubMed  CAS  Google Scholar 

  62. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86(5):749–764. doi:10.1016/j.ajhg.2010.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM (2013) ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 15(11):901–909. doi:10.1038/gim.2013.129

    Article  CAS  PubMed  Google Scholar 

  64. Caruana G, Wong MN, Walker A, Heloury Y, Webb N, Johnstone L, James PA, Burgess T, Bertram JF (2015) Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatric nephrology (Berlin Germany) 30(3):487–495. doi:10.1007/s00467-014-2962-9

    Article  Google Scholar 

  65. Westland R, Verbitsky M, Vukojevic K, Perry BJ, Fasel DA, Zwijnenburg PJ, Bokenkamp A, Gille JJ, Saraga-Babic M, Ghiggeri GM, D’Agati VD, Schreuder MF, Gharavi AG, van Wijk JA, Sanna-Cherchi S (2015) Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney international 88(6):1402–1410. doi:10.1038/ki.2015.239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Verbitsky M, Sanna-Cherchi S, Fasel DA, Levy B, Kiryluk K, Wuttke M, Abraham AG, Kaskel F, Kottgen A, Warady BA, Furth SL, Wong CS, Gharavi AG (2015) Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest 125(5):2171–2178. doi:10.1172/jci80877

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, Lozanovski VJ, Materna-Kiryluk A, Barlassina C, Kini A, Corbani V, Carrea A, Somenzi D, Murtas C, Ristoska-Bojkovska N, Izzi C, Bianco B, Zaniew M, Flogelova H, Weng PL, Kacak N, Giberti S, Gigante M, Arapovic A, Drnasin K, Caridi G, Curioni S, Allegri F, Ammenti A, Ferretti S, Goj V, Bernardo L, Jobanputra V, Chung WK, Lifton RP, Sanders S, State M, Clark LN, Saraga M, Padmanabhan S, Dominiczak AF, Foroud T, Gesualdo L, Gucev Z, Allegri L, Latos-Bielenska A, Cusi D, Scolari F, Tasic V, Hakonarson H, Ghiggeri GM, Gharavi AG (2012) Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet 91(6):987–997. doi:10.1016/j.ajhg.2012.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Materna-Kiryluk A, Kiryluk K, Burgess KE, Bieleninik A, Sanna-Cherchi S, Gharavi AG, Latos-Bielenska A (2014) The emerging role of genomics in the diagnosis and workup of congenital urinary tract defects: a novel deletion syndrome on chromosome 3q13.31-22.1. Pediatric nephrology (Berlin. Germany) 29(2):257–267. doi:10.1007/s00467-013-2625-2

    Google Scholar 

  69. Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, Stajic N, Bogdanovic R, Reutter HM, Kehinde EO, Tasic V, Hildebrandt F (2014) Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. Journal of the American Society of Nephrology : JASN 25(9):1917–1922. doi:10.1681/asn.2013101103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lopez-Rivera E, Liu YP, Verbitsky M, Anderson BR, Capone VP, Otto EA, Yan Z, Mitrotti A, Martino J, Steers NJ, Fasel DA, Vukojevic K, Deng R, Racedo SE, Liu Q, Werth M, Westland R, Vivante A, Makar GS, Bodria M, Sampson MG, Gillies CE, Vega-Warner V, Maiorana M, Petrey DS, Honig B, Lozanovski VJ, Salomon R, Heidet L, Carpentier W, Gaillard D, Carrea A, Gesualdo L, Cusi D, Izzi C, Scolari F, van Wijk JA, Arapovic A, Saraga-Babic M, Saraga M, Kunac N, Samii A, McDonald-McGinn DM, Crowley TB, Zackai EH, Drozdz D, Miklaszewska M, Tkaczyk M, Sikora P, Szczepanska M, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Darlow JM, Puri P, Barton D, Casolari E, Furth SL, Warady BA, Gucev Z, Hakonarson H, Flogelova H, Tasic V, Latos-Bielenska A, Materna-Kiryluk A, Allegri L, Wong CS, Drummond IA, D’Agati V, Imamoto A, Barasch JM, Hildebrandt F, Kiryluk K, Lifton RP, Morrow BE, Jeanpierre C, Papaioannou VE, Ghiggeri GM, Gharavi AG, Katsanis N, Sanna-Cherchi S (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. The New England journal of medicine 376 (8):742–754. doi:10.1056/NEJMoa1609009

  71. Verbitsky M, Kogon AJ, Matheson M, Hooper SR, Wong CS, Warady BA, Furth SL, Gharavi AG (2017) Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. Journal of the American Society of Nephrology : JASN. doi:10.1681/asn.2016101108

    PubMed  Google Scholar 

  72. Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ, Gharavi AG (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatric nephrology (Berlin, Germany) 26. (6):897–903. doi:10.1007/s00467-011-1826-9

  73. Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, Shril S, Hwang DY, Weiss AC, Kaminski MM, Shukrun R, Kemper MJ, Lehnhardt A, Beetz R, Sanna-Cherchi S, Verbitsky M, Gharavi AG, Stuart HM, Feather SA, Goodship JA, Goodship TH, Woolf AS, Westra SJ, Doody DP, Bauer SB, Lee RS, Adam RM, Lu W, Reutter HM, Kehinde EO, Mancini EJ, Lifton RP, Tasic V, Lienkamp SS, Juppner H, Kispert A, Hildebrandt F (2015) Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development. Am J Hum Genet 97(2):291–301. doi:10.1016/j.ajhg.2015.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Weng PL, Sanna-Cherchi S, Hensle T, Shapiro E, Werzberger A, Caridi G, Izzi C, Konka A, Reese AC, Cheng R, Werzberger S, Schlussel RN, Burk RD, Lee JH, Ravazzolo R, Scolari F, Ghiggeri GM, Glassberg K, Gharavi AG (2009) A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13. Journal of the American Society of Nephrology : JASN 20(7):1633–1640. doi:10.1681/asn.2008111199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gelb SR, Shapiro RJ, Thornton WJ (2010) Predicting medication adherence and employment status following kidney transplant: The relative utility of traditional and everyday cognitive approaches. Neuropsychology 24(4):514–526. doi:10.1037/a0018670

    Article  PubMed  Google Scholar 

  76. Ruebner RL, Laney N, Kim JY, Hartung EA, Hooper SR, Radcliffe J, Furth SL (2016) Neurocognitive Dysfunction in Children, Adolescents, and Young Adults With CKD. Am J Kidney Dis 67(4):567–575. doi:10.1053/j.ajkd.2015.08.025

    Article  PubMed  Google Scholar 

  77. Brouhard BH, Donaldson LA, Lawry KW, McGowan KR, Drotar D, Davis I, Rose S, Cohn RA, Tejani A (2000) Cognitive functioning in children on dialysis and post-transplantation. Pediatr Transplant 4(4):261–267

    Article  CAS  PubMed  Google Scholar 

  78. Johnson RJ, Warady BA (2013) Long-term neurocognitive outcomes of patients with end-stage renal disease during infancy. Pediatric nephrology (Berlin Germany) 28(8):1283–1291. doi:10.1007/s00467-013-2458-z

    Article  Google Scholar 

  79. System USRD (2016) 2016 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2016

    Google Scholar 

  80. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW (2013) Chronic kidney disease: global dimension and perspectives. Lancet 382(9888):260–272. doi:10.1016/s0140-6736(13)60687-x

    Article  PubMed  Google Scholar 

  81. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J, Burton PR, Hadley D, McArdle WL, Brown M, Dominiczak A, Newhouse SJ, Samani NJ, Webster J, Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K, Vollenweider P, Waeber G, Waterworth DM, Yuan X, Groop L, Orho-Melander M, Allione A, Di Gregorio A, Guarrera S, Panico S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, Sandhu MS, Luben RN, Crawford GJ, Jousilahti P, Perola M, Boehnke M, Bonnycastle LL, Collins FS, Jackson AU, Mohlke KL, Stringham HM, Valle TT, Willer CJ, Bergman RN, Morken MA, Doring A, Gieger C, Illig T, Meitinger T, Org E, Pfeufer A, Wichmann HE, Kathiresan S, Marrugat J, O’Donnell CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer NB, Hartikainen AL, McCarthy MI, O’Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf U, Syvanen AC, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Dorr M, Ernst F, Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig R, Volker U, Galan P, Gut IG, Hercberg S, Lathrop GM, Zelenika D, Deloukas P, Soranzo N, Williams FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi NG, Volzke H, Uiterwaal CS, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bingham SA, Kooner JS, Connell JM, Bandinelli S, Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Altshuler D, Strachan DP, Laan M, Meneton P, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nature genetics 41(6):666–676. doi:10.1038/ng.361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, Rice K, Morrison AC, Lu Y, Weiss S, Guo X, Palmas W, Martin LW, Chen YD, Surendran P, Drenos F, Cook JP, Auer PL, Chu AY, Giri A, Zhao W, Jakobsdottir J, Lin LA, Stafford JM, Amin N, Mei H, Yao J, Voorman A, Larson MG, Grove ML, Smith AV, Hwang SJ, Chen H, Huan T, Kosova G, Stitziel NO, Kathiresan S, Samani N, Schunkert H, Deloukas P, Li M, Fuchsberger C, Pattaro C, Gorski M, Kooperberg C, Papanicolaou GJ, Rossouw JE, Faul JD, Kardia SL, Bouchard C, Raffel LJ, Uitterlinden AG, Franco OH, Vasan RS, O’Donnell CJ, Taylor KD, Liu K, Bottinger EP, Gottesman O, Daw EW, Giulianini F, Ganesh S, Salfati E, Harris TB, Launer LJ, Dorr M, Felix SB, Rettig R, Volzke H, Kim E, Lee WJ, Lee IT, Sheu WH, Tsosie KS, Edwards DR, Liu Y, Correa A, Weir DR, Volker U, Ridker PM, Boerwinkle E, Gudnason V, Reiner AP, van Duijn CM, Borecki IB, Edwards TL, Chakravarti A, Rotter JI, Psaty BM, Loos RJ, Fornage M, Ehret GB, Newton-Cheh C, Levy D, Chasman DI (2016) Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nature genetics 48(10):1162–1170. doi:10.1038/ng.3660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, NY) 316 (5829):pp 1331–1336. doi:10.1126/science.1142358

    Google Scholar 

  84. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segre AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Bostrom K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jorgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proenca C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparso T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature genetics 42(7):579–589. doi:10.1038/ng.609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, O’Connell JR, Li M, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson AD, Dehghan A, Teumer A, Pare G, Atkinson EJ, Zeller T, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tonjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Boerwinkle E, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Haritunians T, Lumley T, Siscovick D, Psaty BM, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turner ST, Schillert A, Ziegler A, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Illig T, Klopp N, Meisinger C, Wichmann HE, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Schreiber S, Aulchenko YS, Felix JF, Rivadeneira F, Uitterlinden AG, Hofman A, Imboden M, Nitsch D, Brandstatter A, Kollerits B, Kedenko L, Magi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Volzke H, Kroemer HK, Nauck M, Volker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, Kramer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS (2010) New loci associated with kidney function and chronic kidney disease. Nature genetics 42(5):376–384. doi:10.1038/ng.568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Olden M, Teumer A, Bochud M, Pattaro C, Kottgen A, Turner ST, Rettig R, Chen MH, Dehghan A, Bastardot F, Schmidt R, Vollenweider P, Schunkert H, Reilly MP, Fornage M, Launer LJ, Verwoert GC, Mitchell GF, Bis JC, O’Donnell CJ, Cheng CY, Sim X, Siscovick DS, Coresh J, Kao WH, Fox CS, O’Seaghdha CM (2013) Overlap between common genetic polymorphisms underpinning kidney traits and cardiovascular disease phenotypes: the CKDGen consortium. Am J Kidney Dis 61(6):889–898. doi:10.1053/j.ajkd.2012.12.024

    Article  PubMed  PubMed Central  Google Scholar 

  87. Liu CT, Garnaas MK, Tin A, Kottgen A, Franceschini N, Peralta CA, de Boer IH, Lu X, Atkinson E, Ding J, Nalls M, Shriner D, Coresh J, Kutlar A, Bibbins-Domingo K, Siscovick D, Akylbekova E, Wyatt S, Astor B, Mychaleckjy J, Li M, Reilly MP, Townsend RR, Adeyemo A, Zonderman AB, de Andrade M, Turner ST, Mosley TH, Harris TB, Rotimi CN, Liu Y, Kardia SL, Evans MK, Shlipak MG, Kramer H, Flessner MF, Dreisbach AW, Goessling W, Cupples LA, Kao WL, Fox CS (2011) Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. PLoS genetics 7(9):e1002264. doi:10.1371/journal.pgen.1002264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wuttke M, Kottgen A (2016) Insights into kidney diseases from genome-wide association studies. Nat Rev Nephrol 12(9):549–562. doi:10.1038/nrneph.2016.107

    Article  CAS  PubMed  Google Scholar 

  89. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O’Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Sober S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sjogren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimaki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O’Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Kahonen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Kottgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Grassler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Soler Artigas M, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stancakova A, Raffel LJ, Yao J, Kathiresan S, O’Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytikainen LP, Soininen P, Tukiainen T, Wurtz P, Ong RT, Dorr M, Kroemer HK, Volker U, Volzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Jarvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh Levy C, Caulfield D, Johnson MJ T (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478 (7367):103–109. doi:10.1038/nature10405

    Article  CAS  PubMed  Google Scholar 

  90. Wain LV, Verwoert GC, O’Reilly PF, Shi G, Johnson T, Johnson AD, Bochud M, Rice KM, Henneman P, Smith AV, Ehret GB, Amin N, Larson MG, Mooser V, Hadley D, Dorr M, Bis JC, Aspelund T, Esko T, Janssens AC, Zhao JH, Heath S, Laan M, Fu J, Pistis G, Luan J, Arora P, Lucas G, Pirastu N, Pichler I, Jackson AU, Webster RJ, Zhang F, Peden JF, Schmidt H, Tanaka T, Campbell H, Igl W, Milaneschi Y, Hottenga JJ, Vitart V, Chasman DI, Trompet S, Bragg-Gresham JL, Alizadeh BZ, Chambers JC, Guo X, Lehtimaki T, Kuhnel B, Lopez LM, Polasek O, Boban M, Nelson CP, Morrison AC, Pihur V, Ganesh SK, Hofman A, Kundu S, Mattace-Raso FU, Rivadeneira F, Sijbrands EJ, Uitterlinden AG, Hwang SJ, Vasan RS, Wang TJ, Bergmann S, Vollenweider P, Waeber G, Laitinen J, Pouta A, Zitting P, McArdle WL, Kroemer HK, Volker U, Volzke H, Glazer NL, Taylor KD, Harris TB, Alavere H, Haller T, Keis A, Tammesoo ML, Aulchenko Y, Barroso I, Khaw KT, Galan P, Hercberg S, Lathrop M, Eyheramendy S, Org E, Sober S, Lu X, Nolte IM, Penninx BW, Corre T, Masciullo C, Sala C, Groop L, Voight BF, Melander O, O’Donnell CJ, Salomaa V, d’Adamo AP, Fabretto A, Faletra F, Ulivi S, Del Greco F, Facheris M, Collins FS, Bergman RN, Beilby JP, Hung J, Musk AW, Mangino M, Shin SY, Soranzo N, Watkins H, Goel A, Hamsten A, Gider P, Loitfelder M, Zeginigg M, Hernandez D, Najjar SS, Navarro P, Wild SH, Corsi AM, Singleton A, de Geus EJ, Willemsen G, Parker AN, Rose LM, Buckley B, Stott D, Orru M, Uda M, van der Klauw MM, Zhang W, Li X, Scott J, Chen YD, Burke GL, Kahonen M, Viikari J, Doring A, Meitinger T, Davies G, Starr JM, Emilsson V, Plump A, Lindeman JH, Hoen PA, Konig IR, Felix JF, Clarke R, Hopewell JC, Ongen H, Breteler M, Debette S, Destefano AL, Fornage M, Mitchell GF, Smith NL, Holm H, Stefansson K, Thorleifsson G, Thorsteinsdottir U, Samani NJ, Preuss M, Rudan I, Hayward C, Deary IJ, Wichmann HE, Raitakari OT, Palmas W, Kooner JS, Stolk RP, Jukema JW, Wright AF, Boomsma DI, Bandinelli S, Gyllensten UB, Wilson JF, Ferrucci L, Schmidt R, Farrall M, Spector TD, Palmer LJ, Tuomilehto J, Pfeufer A, Gasparini P, Siscovick D, Altshuler D, Loos RJ, Toniolo D, Snieder H, Gieger C, Meneton P, Wareham NJ, Oostra BA, Metspalu A, Launer L, Rettig R, Strachan DP, Beckmann JS, Witteman JC, Erdmann J, van Dijk KW, Boerwinkle E, Boehnke M, Ridker PM, Jarvelin MR, Chakravarti A, Abecasis GR, Gudnason V, Newton-Cheh C, Levy D, Munroe PB, Psaty BM, Caulfield MJ, Rao DC, Tobin MD, Elliott P, van Duijn CM (2011) Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nature genetics 43(10):1005–1011. doi:10.1038/ng.922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F, Takahashi A, Maeda S, Tsunoda T, Chen P, Lim SC, Wong TY, Liu J, Young TL, Aung T, Seielstad M, Teo YY, Kim YJ, Lee JY, Han BG, Kang D, Chen CH, Tsai FJ, Chang LC, Fann SJ, Mei H, Rao DC, Hixson JE, Chen S, Katsuya T, Isono M, Ogihara T, Chambers JC, Zhang W, Kooner JS, Albrecht E, Yamamoto K, Kubo M, Nakamura Y, Kamatani N, Kato N, He J, Chen YT, Cho YS, Tai ES, Tanaka T (2012) Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. Nature genetics 44(8):904–909. doi:10.1038/ng.2352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shved N, Warsow G, Eichinger F, Hoogewijs D, Brandt S, Wild P, Kretzler M, Cohen CD, Lindenmeyer MT (2017) Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts. Scientific reports 7(1):8576. doi:10.1038/s41598-017-08492-y

    Article  PubMed  PubMed Central  Google Scholar 

  93. Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KE, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M (2013) Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney international 83(4):749–756. doi:10.1038/ki.2012.428

    Article  PubMed  PubMed Central  Google Scholar 

  94. Barisoni L, Nast CC, Jennette JC, Hodgin JB, Herzenberg AM, Lemley KV, Conway CM, Kopp JB, Kretzler M, Lienczewski C, Avila-Casado C, Bagnasco S, Sethi S, Tomaszewski J, Gasim AH, Hewitt SM (2013) Digital pathology evaluation in the multicenter Nephrotic Syndrome Study Network (NEPTUNE). Clinical journal of the American Society of Nephrology : CJASN 8(8):1449–1459. doi:10.2215/cjn.08370812

    Article  PubMed  PubMed Central  Google Scholar 

  95. Harding SD, Armit C, Armstrong J, Brennan J, Cheng Y, Haggarty B, Houghton D, Lloyd-MacGilp S, Pi X, Roochun Y, Sharghi M, Tindal C, McMahon AP, Gottesman B, Little MH, Georgas K, Aronow BJ, Potter SS, Brunskill EW, Southard-Smith EM, Mendelsohn C, Baldock RA, Davies JA, Davidson D (2011) The GUDMAP database–an online resource for genitourinary research. Development (Cambridge England) 138(13):2845–2853. doi:10.1242/dev.063594

    Article  CAS  Google Scholar 

  96. Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS, Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP (2013) Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 93(4):631–640. doi:10.1016/j.ajhg.2013.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hennekam RC, Biesecker LG (2012) Next-generation sequencing demands next-generation phenotyping. Hum Mutat 33(5):884–886. doi:10.1002/humu.22048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunso S, Svendsen JH, Olesen MS (2013) New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 21(9):918–928. doi:10.1038/ejhg.2012.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Xue Y, Chen Y, Ayub Q, Huang N, Ball EV, Mort M, Phillips AD, Shaw K, Stenson PD, Cooper DN, Tyler-Smith C (2012) Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am J Hum Genet 91(6):1022–1032. doi:10.1016/j.ajhg.2012.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Burke W, Antommaria AH, Bennett R, Botkin J, Clayton EW, Henderson GE, Holm IA, Jarvik GP, Khoury MJ, Knoppers BM, Press NA, Ross LF, Rothstein MA, Saal H, Uhlmann WR, Wilfond B, Wolf SM, Zimmern R (2013) Recommendations for returning genomic incidental findings? We need to talk! Genet Med 15(11):854–859. doi:10.1038/gim.2013.113

    Article  CAS  PubMed  Google Scholar 

  101. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7):565–574. doi:10.1038/gim.2013.73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, Barrett JC, Biesecker LG, Conrad DF, Cooper GM, Cox NJ, Daly MJ, Gerstein MB, Goldstein DB, Hirschhorn JN, Leal SM, Pennacchio LA, Stamatoyannopoulos JA, Sunyaev SR, Valle D, Voight BF, Winckler W, Gunter C (2014) Guidelines for investigating causality of sequence variants in human disease. Nature 508(7497):469–476. doi:10.1038/nature13127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 2015 APS (2015) ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med 17 (1):68–69. doi:10.1038/gim.2014.151

    Article  Google Scholar 

  104. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. doi:10.1038/nature19057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337(6090):64–69. doi:10.1126/science.1219240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, Jostins L, Habegger L, Pickrell JK, Montgomery SB, Albers CA, Zhang ZD, Conrad DF, Lunter G, Zheng H, Ayub Q, DePristo MA, Banks E, Hu M, Handsaker RE, Rosenfeld JA, Fromer M, Jin M, Mu XJ, Khurana E, Ye K, Kay M, Saunders GI, Suner MM, Hunt T, Barnes IH, Amid C, Carvalho-Silva DR, Bignell AH, Snow C, Yngvadottir B, Bumpstead S, Cooper DN, Xue Y, Romero IG, Wang J, Li Y, Gibbs RA, McCarroll SA, Dermitzakis ET, Pritchard JK, Barrett JC, Harrow J, Hurles ME, Gerstein MB, Tyler-Smith C (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335(6070):823–828. doi:10.1126/science.1215040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Manrai AK, Funke BH, Rehm HL, Olesen MS, Maron BA, Szolovits P, Margulies DM, Loscalzo J, Kohane IS (2016) Genetic Misdiagnoses and the Potential for Health Disparities. The New England journal of medicine 375(7):655–665. doi:10.1056/NEJMsa1507092

    Article  PubMed  PubMed Central  Google Scholar 

  108. Van Ness B (2008) Genomic research and incidental findings. J Law Med Ethics 36(2):292–297. doi:10.1111/j.1748-720X.2008.00272.x (212)

    Article  PubMed  PubMed Central  Google Scholar 

  109. Fabsitz RR, McGuire A, Sharp RR, Puggal M, Beskow LM, Biesecker LG, Bookman E, Burke W, Burchard EG, Church G, Clayton EW, Eckfeldt JH, Fernandez CV, Fisher R, Fullerton SM, Gabriel S, Gachupin F, James C, Jarvik GP, Kittles R, Leib JR, O’Donnell C, O’Rourke PP, Rodriguez LL, Schully SD, Shuldiner AR, Sze RK, Thakuria JV, Wolf SM, Burke GL (2010) Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ Cardiovasc Genet 3(6):574–580. doi:10.1161/circgenetics.110.958827

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hudson KL (2011) Genomics, health care, and society. The New England journal of medicine 365(11):1033–1041. doi:10.1056/NEJMra1010517

    Article  CAS  PubMed  Google Scholar 

  111. Simon CM, Williams JK, Shinkunas L, Brandt D, Daack-Hirsch S, Driessnack M (2011) Informed consent and genomic incidental findings: IRB chair perspectives. J Empir Res Hum Res Ethics 6(4):53–67. doi:10.1525/jer.2011.6.4.53

    Article  PubMed  PubMed Central  Google Scholar 

  112. Wolf SM, Crock BN, Van Ness B, Lawrenz F, Kahn JP, Beskow LM, Cho MK, Christman MF, Green RC, Hall R, Illes J, Keane M, Knoppers BM, Koenig BA, Kohane IS, Leroy B, Maschke KJ, McGeveran W, Ossorio P, Parker LS, Petersen GM, Richardson HS, Scott JA, Terry SF, Wilfond BS, Wolf WA (2012) Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med 14(4):361–384. doi:10.1038/gim.2012.23

    Article  PubMed  PubMed Central  Google Scholar 

  113. Fullerton SM, Wolf WA, Brothers KB, Clayton EW, Crawford DC, Denny JC, Greenland P, Koenig BA, Leppig KA, Lindor NM, McCarty CA, McGuire AL, McPeek Hinz ER, Mirel DB, Ramos EM, Ritchie MD, Smith ME, Waudby CJ, Burke W, Jarvik GP (2012) Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network. Genet Med 14(4):424–431. doi:10.1038/gim.2012.15

    Article  PubMed  PubMed Central  Google Scholar 

  114. Knoppers BM, Deschenes M, Zawati MH, Tasse AM (2013) Population studies: return of research results and incidental findings Policy Statement. Eur J Hum Genet 21(3):245–247. doi:10.1038/ejhg.2012.152

    Article  PubMed  Google Scholar 

  115. Pereira S, Oliver Robinson J, McGuire AL (2016) Return of individual genomic research results: what do consent forms tell participants? Eur J Hum Genet 24(11):1524–1529. doi:10.1038/ejhg.2016.76

    Article  PubMed  PubMed Central  Google Scholar 

  116. O’Doherty KC, Christofides E, Yen J, Bentzen HB, Burke W, Hallowell N, Koenig BA, Willison DJ (2016) If you build it, they will come: unintended future uses of organised health data collections. BMC Med Ethics 17(1):54. doi:10.1186/s12910-016-0137-x

    Article  PubMed  PubMed Central  Google Scholar 

  117. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Herman GE, Hufnagel SB, Klein TE, Korf BR, McKelvey KD, Ormond KE, Richards CS, Vlangos CN, Watson M, Martin CL, Miller DT (2016) 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. doi:10.1038/gim.2016.190

    PubMed  Google Scholar 

  118. Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG (2012) Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet 91(1):97–108. doi:10.1016/j.ajhg.2012.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ding LE, Burnett L, Chesher D (2015) The impact of reporting incidental findings from exome and whole-genome sequencing: predicted frequencies based on modeling. Genet Med 17(3):197–204. doi:10.1038/gim.2014.94

    Article  PubMed  Google Scholar 

  120. Gambin T, Jhangiani SN, Below JE, Campbell IM, Wiszniewski W, Muzny DM, Staples J, Morrison AC, Bainbridge MN, Penney S, McGuire AL, Gibbs RA, Lupski JR, Boerwinkle E (2015) Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med 7(1):54. doi:10.1186/s13073-015-0171-1

    Article  PubMed  PubMed Central  Google Scholar 

  121. Wolf SM, Annas GJ, Elias S (2013) Point-counterpoint. Patient autonomy and incidental findings in clinical genomics. Science 340(6136):1049–1050. doi:10.1126/science.1239119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ross LF, Rothstein MA, Clayton EW (2013) Mandatory extended searches in all genome sequencing: “incidental findings,” patient autonomy, and shared decision making. Jama 310(4):367–368. doi:10.1001/jama.2013.41700

    Article  CAS  PubMed  Google Scholar 

  123. Evans BJ (2013) Minimizing liability risks under the ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Genet Med 15(12):915–920. doi:10.1038/gim.2013.135

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jarvik GP, Amendola LM, Berg JS, Brothers K, Clayton EW, Chung W, Evans BJ, Evans JP, Fullerton SM, Gallego CJ, Garrison NA, Gray SW, Holm IA, Kullo IJ, Lehmann LS, McCarty C, Prows CA, Rehm HL, Sharp RR, Salama J, Sanderson S, Van Driest SL, Williams MS, Wolf SM, Wolf WA, Burke W (2014) Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am J Hum Genet 94(6):818–826. doi:10.1016/j.ajhg.2014.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rigter T, Henneman L, Kristoffersson U, Hall A, Yntema HG, Borry P, Tonnies H, Waisfisz Q, Elting MW, Dondorp WJ, Cornel MC (2013) Reflecting on earlier experiences with unsolicited findings: points to consider for next-generation sequencing and informed consent in diagnostics. Hum Mutat 34(10):1322–1328. doi:10.1002/humu.22370

    Article  PubMed  PubMed Central  Google Scholar 

  126. Khan A, Capps BJ, Sum MY, Kuswanto CN, Sim K (2014) Informed consent for human genetic and genomic studies: a systematic review. Clin Genet 86(3):199–206. doi:10.1111/cge.12384

    Article  CAS  PubMed  Google Scholar 

  127. Botkin JR, Belmont JW, Berg JS, Berkman BE, Bombard Y, Holm IA, Levy HP, Ormond KE, Saal HM, Spinner NB, Wilfond BS, McInerney JD (2015) Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. Am J Hum Genet 97(1):6–21. doi:10.1016/j.ajhg.2015.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Clayton EW, McCullough LB, Biesecker LG, Joffe S, Ross LF, Wolf SM (2014) Addressing the ethical challenges in genetic testing and sequencing of children. Am J Bioeth 14(3):3–9. doi:10.1080/15265161.2013.879945

    Article  PubMed  PubMed Central  Google Scholar 

  129. Anderson JA, Hayeems RZ, Shuman C, Szego MJ, Monfared N, Bowdin S, Zlotnik Shaul R, Meyn MS (2015) Predictive genetic testing for adult-onset disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines. Clin Genet 87(4):301–310. doi:10.1111/cge.12460

    Article  CAS  PubMed  Google Scholar 

  130. Knoppers BM, Zawati MH, Senecal K (2015) Return of genetic testing results in the era of whole-genome sequencing. Nat Rev Genet 16(9):553–559. doi:10.1038/nrg3960

    Article  CAS  PubMed  Google Scholar 

  131. Norris K, Nissenson AR (2008) Race, gender, and socioeconomic disparities in CKD in the United States. Journal of the American Society of Nephrology : JASN 19(7):1261–1270. doi:10.1681/asn.2008030276

    Article  PubMed  Google Scholar 

  132. Popejoy AB, Fullerton SM (2016) Genomics is failing on diversity. Nature 538(7624):161–164. doi:10.1038/538161a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tan DS, Mok TS, Rebbeck TR (2016) Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography. J Clin Oncol 34(1):91–101. doi:10.1200/jco.2015.62.0096

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This review was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; Grant no. 1T32DK108741-01), the National Institutes of Health (NIH; Grant no. 1F30DK116473), and the National Human Genome Research Institute (NHGRI; Grant no. 5U01HG008680-03). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Ave, Room 413, New York, NY, 10032, USA

    Jordan G. Nestor, Emily E. Groopman & Ali G. Gharavi

Authors
  1. Jordan G. Nestor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily E. Groopman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ali G. Gharavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali G. Gharavi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This review does not involve human participants and/or animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nestor, J.G., Groopman, E.E. & Gharavi, A.G. Towards precision nephrology: the opportunities and challenges of genomic medicine. J Nephrol 31, 47–60 (2018). https://doi.org/10.1007/s40620-017-0448-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-017-0448-0

Keywords

Search

Navigation