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  • Review Article
  • Published:

Genetic, environmental, and epigenetic factors involved in CAKUT

Nature Reviews Nephrology volume 11, pages 720–731 (2015)Cite this article

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This article has been updated

Key Points

  • Approaches to discover genetic causes of congenital anomalies of the kidney and urinary tract (CAKUT) include candidate gene and whole exome sequencing, and genome-wide linkage and copy number variant (CNV) analyses

  • The majority of sporadic cases of CAKUT cannot yet be explained by monogenic causes

  • Certain CNVs are associated with an elevated risk of CAKUT, indicating that CNV analysis should become part of the diagnostic procedure

  • Chromosomal imbalances and single nucleotide variants in non-coding regions contribute to congenital malformations, suggesting that genomic regulatory elements might also function in the pathogenesis of CAKUT

  • Epigenetic and gestational environmental risk factors can influence kidney development and/or fibrosis and might also increase susceptibility to CAKUT

  • Collaborative efforts are needed to collect large cohorts of patients with CAKUT and to integrate the data from epidemiologic, clinical, genomic, epigenomic, transcriptomic, and proteomic studies

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a spectrum of structural renal malformations and are the leading cause of end-stage renal disease in children. The genetic diagnosis of CAKUT has proven to be challenging due to genetic and phenotypic heterogeneity and incomplete genetic penetrance. Monogenic causes of CAKUT have been identified using different approaches, including single gene screening, and gene panel and whole exome sequencing. The majority of the identified mutations, however, lack substantial evidence to support a pathogenic role in CAKUT. Copy number variants or single nucleotide variants that are associated with CAKUT have also been identified. Numerous studies support the influence of epigenetic and environmental factors on kidney development and the natural history of CAKUT, suggesting that the pathogenesis of this syndrome is multifactorial. In this Review we describe the current knowledge regarding the genetic susceptibility underlying CAKUT and the approaches used to investigate the genetic basis of CAKUT. We outline the associated environmental risk factors and epigenetic influences on CAKUT and discuss the challenges and strategies used to fully address the involvement and interplay of these factors in the pathogenesis of the disease.

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Figure 1: Illustrative 3D models of congenital abnormalities of the kidney and urinary tract (CAKUT) that were created using the modelling tools ZBrush (Pixologic, Inc.) and 3ds Max (Autodesk, Inc.), to illustrate the phenotypic spectrum of CAKUT.
Figure 2: The potential effect of the interplay between environmental, epigenetic, and genetic factors on kidney development.

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Change history

  • 24 November 2015

    In the HTML and PDF versions of this article originally published online, the black arrow was missing from the 'Posterior urethral valves' panel in Figure 1. This error has now been corrected in print and online.

References

  1. Brown, T., Mandell, J. & Lebowitz, R. L. Neonatal hydronephrosis in the era of sonography. Am. J. Roentgenol. 148, 959–963 (1987).

    Article  CAS  Google Scholar 

  2. Queisser-Luft, A., Stolz, G., Wiesel, A., Schlaefer, K. & Spranger, J. Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998). Arch. Gynecol. Obstet. 266, 163–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Sanna-Cherchi, S. et al. Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr. Nephrol. 22, 1675–1684 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pope, J. C. 4th, Brock, J. W. 3rd, Adams, M. C., Stephens, F. D. & Ichikawa, I. How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J. Am. Soc. Nephrol. 10, 2018–2028 (1999).

    PubMed  Google Scholar 

  5. Vivante, A., Kohl, S., Hwang, D. Y., Dworschak, G. C. & Hildebrandt, F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr. Nephrol. 29, 695–704 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Blake, J. & Rosenblum, N. D. Renal branching morphogenesis: morphogenetic and signaling mechanisms. Semin. Cell Dev. Biol. 36, 2–12 (2014).

    Article  PubMed  Google Scholar 

  8. Chesnaye, N. et al. Demographics of paediatric renal replacement therapy in Europe: a report of the ESPN/ERA–EDTA registry. Pediatr. Nephrol. 29, 2403–2410 (2014).

    Article  PubMed  Google Scholar 

  9. Wuhl, E. et al. Timing and outcome of renal replacement therapy in patients with congenital malformations of the kidney and urinary tract. Clin. J. Am. Soc. Nephrol. 8, 67–74 (2013).

    Article  PubMed  Google Scholar 

  10. Kerecuk, L., Schreuder, M. F. & Woolf, A. S. Renal tract malformations: perspectives for nephrologists. Nat. Clin. Pract. Nephrol. 4, 312–325 (2008).

    Article  PubMed  Google Scholar 

  11. Stoll, C., Dott, B., Alembik, Y. & Roth, M. P. Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT). Eur. J. Med. Genet. 57, 322–328 (2014).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. 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 

  14. Monn, E. & Nordshus, T. Hereditary renal adysplasia. Acta. Paediatr. Scand. 73, 278–280 (1984).

    Article  CAS  PubMed  Google Scholar 

  15. McPherson, E. et al. Dominantly inherited renal adysplasia. Am. J. Med. Genet. 26, 863–872 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Kaplan, B. S., Milner, L. S., Jequier, S., Kaplan, P. & de Chadarevian, J. P. Autosomal dominant inheritance of small kidneys. Am. J. Med. Genet. 32, 120–126 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Doray, B., Gasser, B., Reinartz, I. & Stoll, C. Hereditary renal adysplasia in a three generations family. Genet. Couns. 10, 251–257 (1999).

    CAS  PubMed  Google Scholar 

  18. Sanyanusin, P. et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat. Genet. 9, 358–364 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Weber, S. et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J. Am. Soc. Nephrol. 17, 2864–2870 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Thomas, R. et al. HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr. Nephrol. 26, 897–903 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Hwang, D. Y. et al. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 85, 1429–1433 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Exome Aggregation Consortium (ExAC), http://exac.broadinstitute.org [June 2015 accessed].

  26. Weber, S. et al. SIX2 and BMP4 mutations associate with anomalous kidney development. J. Am. Soc. Nephrol. 19, 891–903 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Skinner, M. A., Safford, S. D., Reeves, J. G., Jackson, M. E. & Freemerman, A. J. Renal aplasia in humans is associated with RET mutations. Am. J. Hum. Genet. 82, 344–351 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gimelli, S. et al. Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. Hum. Mutat. 31, 1352–1359 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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 

  30. Coon, K. D. et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J. Clin. Psychiatry 68, 613–618 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Julier, C. et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155–159 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Williams, G., Fletcher, J. T., Alexander, S. I. & Craig, J. C. Vesicoureteral reflux. J. Am. Soc. Nephrol. 19, 847–862 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Weng, P. L. et al. A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13. J. Am. Soc. Nephrol. 20, 1633–1640 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ashraf, S. et al. Mapping of a new locus for congenital anomalies of the kidney and urinary tract on chromosome 8q24. Nephrol. Dial. Transplant. 25, 1496–1501 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Sanna-Cherchi, S. et al. Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32–33 Am. J. Hum. Genet. 80, 539–49 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chatterjee, R. et al. Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum. Genet. 131, 1725–1738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kohl, S. et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 25, 1917–1922 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Humbert, C. et al. Integrin alpha 8 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 

  40. Saisawat, P. et al. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int. 85, 1310–1317 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. PhenomeCentral Version 1.0 Milestone-7. A hub for secure data sharing within the rare disorder community [online], (2015).

  42. Swaminathan, G. J. et al. DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet. 21, R37–44 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rehm, H. L. et al. ClinGen - The Clinical Genome Resource. N. Engl. J. Med. (2015).

  44. Fokkema, I. F. et al. LOVD v.2.0: the next generation in gene variant databases. Hum. Mutat. 32, 557–563 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Matchmaker Exchange. Genomic discovery through the exchange of phenotypic & genotypic profiles [online], (2015).

  46. 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 

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

    Article  CAS  PubMed  Google Scholar 

  48. Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860–863 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bower, M. et al. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum. Mutat. 33, 457–466 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Serra-Juhe, C. et al. Contribution of rare copy number variants to isolated human malformations. PLoS ONE 7, e45530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Anad, F. et al. Alagille syndrome and deletion of 20p. J. Med. Genet. 27, 729–737 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Davies, A. F. et al. Delineation of two distinct 6p deletion syndromes. Hum. Genet. 104, 64–72 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Kirk, J. M. et al. Unilateral renal aplasia in X-linked Kallmann's syndrome. Clin. Genet. 46, 260–262 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Mefford, H. C. et al. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am. J. Hum. Genet. 81, 1057–1069 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nat. Rev. Genet. 12, 363–376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. de Ligt, J. et al. Detection of clinically relevant copy number variants with whole-exome sequencing. Hum. Mutat. 34, 1439–1448 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Hoefele, J. et al. A novel interstitial deletion of 10q24.2q24.32 in a patient with renal coloboma syndrome. Eur. J. Med. Genet. 55, 211–215 (2012).

    Article  PubMed  Google Scholar 

  59. 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 

  60. Caruana, G. et al. Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatr. Nephrol. 30, 487–495 (2015).

    Article  PubMed  Google Scholar 

  61. Uchiyama, Y. et al. Kif26b, a kinesin family gene, regulates adhesion of the embryonic kidney mesenchyme. Proc. Natl Acad. Sci. USA 107, 9240–9245 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Selleri, L. et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development 128, 3543–3557 (2001).

    CAS  PubMed  Google Scholar 

  63. Vulto-van Silfhout, A. T. et al. An update on ECARUCA, the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations. Eur. J. Med. Genet. 56, 471–474 (2013).

    Article  PubMed  Google Scholar 

  64. Riggs, E. R., Jackson, L., Miller, D. T. & Van Vooren, S. Phenotypic information in genomic variant databases enhances clinical care and research: the International Standards for Cytogenomic Arrays Consortium experience. Hum. Mutat. 33, 787–796 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  65. MacDonald, J. R., Ziman, R., Yuen, R. K., Feuk, L. & Scherer, S. W. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 42, D986–992 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Ibn-Salem, J. et al. Deletions of chromosomal regulatory boundaries are associated with congenital disease. Genome Biol. 15, 423 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kloosterman, W. P. & Hochstenbach, R. Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease. Mol. Cytogenet. 7, 100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dauber, A. et al. SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant. Am. J. Hum. Genet. 93, 798–811 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Francioli, L. C. et al. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).

    Article  CAS  Google Scholar 

  70. Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Weedon, M. N. et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat. Genet. 46, 61–64 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Smemo, S. et al. Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum. Mol. Genet. 21, 3255–3263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li, Q. Y. et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat. Genet. 15, 21–29 (1997).

    Article  PubMed  Google Scholar 

  74. Kawahara, Y. Human diseases caused by germline and somatic abnormalities in microRNA and microRNA-related genes. Congenit. Anom. (Kyoto) 54, 12–21 (2014).

    Article  CAS  Google Scholar 

  75. Drake, K. M. et al. Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562. Clin. Cancer Res. 15, 5985–5992 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mencia, A. et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat. Genet. 41, 609–613 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Patel, V. et al. MicroRNAs regulate renal tubule maturation through modulation of Pkd1. J. Am. Soc. Nephrol. 23, 1941–1948 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bartram, M. P. et al. Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT). J. Mol. Med. 91, 739–748 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Ho, J. et al. Podocyte-specific loss of functional microRNAs leads to rapid glomerular and tubular injury. J. Am. Soc. Nephrol. 19, 2069–2075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sun, H. et al. MicroRNA-17 post-transcriptionally regulates polycystic kidney disease-2 gene and promotes cell proliferation. Mol. Biol. Rep. 37, 2951–2958 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Patel, V. et al. miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. Proc. Natl Acad. Sci. USA 110, 10765–10770 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Thiagarajan, R. D. et al. Refining transcriptional programs in kidney development by integration of deep RNA-sequencing and array-based spatial profiling. BMC Genomics 12, 441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10, 57–63 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cordell, H. J. et al. Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux. J. Am. Soc. Nephrol. 21, 113–123 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. van Eerde, A. M. et al. Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients. PLoS ONE 7, e31327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 

  87. Reis, G. S. et al. Study of the association between the BMP4 gene and congenital anomalies of the kidney and urinary tract. J. Pediatr. (Rio J.) 90, 58–64 (2014).

    Article  Google Scholar 

  88. Miranda, D. M. et al. Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients. Nephrology (Carlton) 19, 714–720 (2014).

    Article  CAS  Google Scholar 

  89. Darlow, J. M. et al. A new genome scan for primary nonsyndromic vesicoureteric reflux emphasizes high genetic heterogeneity and shows linkage and association with various genes already implicated in urinary tract development. Mol. Genet. Genomic Med. 2, 7–29 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. van der Zanden, L. F. et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat. Genet. 43, 48–50 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kopp, J. B. et al. Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS clinical trial. J. Am. Soc. Nephrol. (2015).

  93. Kottgen, A. et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41, 712–717 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kottgen, A. et al. New loci associated with kidney function and chronic kidney disease. Nat. Genet. 42, 376–384 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Woroniecki, R., Gaikwad, A. B. & Susztak, K. Fetal environment, epigenetics, and pediatric renal disease. Pediatr. Nephrol. 26, 705–711 (2011).

    Article  PubMed  Google Scholar 

  96. Parikh, C. R., McCall, D., Engelman, C. & Schrier, R. W. Congenital renal agenesis: case-control analysis of birth characteristics. Am. J. Kidney Dis. 39, 689–694 (2002).

    Article  PubMed  Google Scholar 

  97. Hsu, C. W., Yamamoto, K. T., Henry, R. K., De Roos, A. J. & Flynn, J. T. Prenatal risk factors for childhood CKD. J. Am. Soc. Nephrol. 25, 2105–2111 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Dart, A. B., Ruth, C. A., Sellers, E. A., Au, W. & Dean, H. J. Maternal diabetes mellitus and congenital anomalies of the kidney and urinary tract (CAKUT) in the child. Am. J. Kidney Dis. 65, 684–691 (2015).

    Article  PubMed  Google Scholar 

  99. Amri, K., Freund, N., Vilar, J., Merlet-Benichou, C. & Lelievre-Pegorier, M. Adverse effects of hyperglycemia on kidney development in rats: in vivo and in vitro studies. Diabetes 48, 2240–2245 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Hoppe, C. C., Evans, R. G., Bertram, J. F. & Moritz, K. M. Effects of dietary protein restriction on nephron number in the mouse. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1768–R1774 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Wilkinson, L. J. et al. Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric beta-catenin signaling. Kidney Int. 87, 975–983 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Feil, R. & Fraga, M. F. Epigenetics and the environment: emerging patterns and implications. Nat. Rev. Genet. 13, 97–109 (2011).

    Article  CAS  Google Scholar 

  103. Oberlander, T. F. et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3, 97–106 (2008).

    Article  PubMed  Google Scholar 

  104. Teh, A. L. et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 24, 1064–1074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sun, G. et al. Epigenetic histone methylation modulates fibrotic gene expression. J. Am. Soc. Nephrol. 21, 2069–2080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ko, Y. A. et al. Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol. 14, R108 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Patel, S. R., Kim, D., Levitan, I. & Dressler, G. R. The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev. Cell 13, 580–592 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lefevre, G. M., Patel, S. R., Kim, D., Tessarollo, L. & Dressler, G. R. Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic disease phenotype. PLoS Genet. 6, e1001142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Castillo-Fernandez, J. E., Spector, T. D. & Bell, J. T. Epigenetics of discordant monozygotic twins: implications for disease. Genome Med. 6, 60 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Jin, M. et al. Genomic and epigenomic analyses of monozygotic twins discordant for congenital renal agenesis. Am. J. Kidney Dis. 64, 119–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Gribouval, O. et al. Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis. Hum. Mutat. 33, 316–326 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Gribouval, O. et al. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat. Genet. 37, 964–968 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Weber, S. et al. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am. J. Hum. Genet. 89, 668–674 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Alazami, A. M. et al. FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. Am. J. Hum. Genet. 85, 414–418 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Vogel, M. J. et al. Mutations in GRIP1 cause Fraser syndrome. J. Med. Genet. 49, 303–306 (2012).

    Article  PubMed  Google Scholar 

  116. Daly, S. B. et al. Mutations in HPSE2 cause urofacial syndrome. Am. J. Hum. Genet. 86, 963–969 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Li, Y. et al. LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am. J. Hum. Genet. 86, 696–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tufan, F. et al. Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome. Am. J. Med. Genet. A 136, 185–189 (2005).

    Article  PubMed  Google Scholar 

  119. Kraus, M. R. et al. Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia. Hum. Mutat. 33, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Tabatabaeifar, M. et al. Functional analysis of BMP4 mutations identified in pediatric CAKUT patients. Pediatr. Nephrol. 24, 2361–2368 (2009).

    Article  PubMed  Google Scholar 

  121. Unger, S. et al. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nat. Genet. 40, 287–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Trarbach, E. B. et al. Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. J. Clin. Endocrinol. Metab. 95, 3491–3496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dode, C. et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat. Genet. 33, 463–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Ali, A. et al. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum. Mol. Genet. 16, 265–275 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Johnston, J. J. et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am. J. Hum. Genet. 76, 609–622 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Heidet, L. et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin. J. Am. Soc. Nephrol. 5, 1079–1090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Barbacci, E. et al. HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum. Mol. Genet. 13, 3139–3149 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Guegan, K., Stals, K., Day, M., Turnpenny, P. & Ellard, S. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome. Clin. Genet. 82, 33–40 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Albuisson, J. et al. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum. Mutat. 25, 98–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Kamath, B. M. et al. NOTCH2 mutations in Alagille syndrome. J. Med. Genet. 49, 138–144 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Favor, J. et al. The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc. Natl Acad. Sci. USA 93, 13870–13875 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. Meeus, L. et al. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocrinol. Metab. 89, 4285–4291 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Bertoli-Avella, A. M. et al. ROBO2 gene variants are associated with familial vesicoureteral reflux. J. Am. Soc. Nephrol. 19, 825–831 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yoshida, Y. et al. Increased levels of pigment epithelium-derived factor in aqueous humor of patients with uveitis. Br. J. Ophthalmol. 91, 149–150 (2007).

    Article  PubMed  Google Scholar 

  135. Hanchate, N. K. et al. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 8, e1002896 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ruf, R. G. et al. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc. Natl Acad. Sci. USA 101, 8090–8095 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Hoskins, B. E. et al. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am. J. Hum. Genet. 80, 800–804 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Li, H., Sheridan, R. & Williams, T. Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2α DNA-binding domain. Hum. Mol. Genet. 22, 3195–3206 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jenkins, D. et al. De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure. J. Am. Soc. Nephrol. 16, 2141–2149 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Realexis Koutsavaki Christofides for modelling the congenital abnormalities of the kidney and urinary tract phenotypes in a 3D format and kindly providing the images shown in Figure 1. The authors' research is supported by grants from the European Community's Seventh Framework Programme FP7/2009 under grant agreement 305608 (EURenOmics).

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Authors and Affiliations

  1. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, Utrecht, 3508 AB, Netherlands

    Nayia Nicolaou, Kirsten Y. Renkema & Nine V. A. M. Knoers

  2. Department of Human Genetics, Radboud University Medical Center, PO Box 9101, Nijmegen, 6500 HB, Netherlands

    Ernie M. H. F. Bongers

  3. Department of Nephrology and Hypertension, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 AB, Netherlands

    Rachel H. Giles

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N.N. researched the data for and wrote the article. All authors provided a substantial contribution to discussion of the content and to review and/or editing of the manuscript before submission.

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Correspondence to Nine V. A. M. Knoers.

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Nicolaou, N., Renkema, K., Bongers, E. et al. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol 11, 720–731 (2015). https://doi.org/10.1038/nrneph.2015.140

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