Genetic, environmental, and epigenetic factors involved in CAKUT.
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.
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands.
Nayia
N
Nicolaou
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands.
Kirsten Y
KY
Renkema
Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, Netherlands.
Ernie M H F
EM
Bongers
Department of Nephrology and Hypertension, University Medical Center Utrecht, PO Box 85500, 3508 AB, Utrecht, Netherlands.
Rachel H
RH
Giles
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands.
Nine V A M
NV
Knoers
D000013:Congenital Abnormalities / Q000209:etiology / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects; D044127:Epigenesis, Genetic; D006801:Humans; D007668:Kidney / Q000002:abnormalities; D014551:Urinary Tract / Q000002:abnormalities*