Genetic basis of human congenital anomalies of the kidney and urinary tract

Sanna‐Cherchi, Simone; Westland, Rik; Ghiggeri, Gian Marco; Gharavi, Ali G.

doi:10.1172/jci95300

Cited by 103 publications

(104 citation statements)

References 166 publications

(214 reference statements)

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“…3,13 With the exception of the cohort of patients with urinary stone disease, in which all three patients had mutations in AGXT, the molecular diagnostic rate for each clinical group in our study was slightly higher than, but overall similar to, those that have been previously reported. [3][4][5][6][7][8][9][10][11][12][13][14][15]19 Although research-based genetic testing for most of our patients was performed after kidney transplantation, we identified both retrospective and prospective clinical implications for five patients in whom a molecular diagnosis was established. In 11 cases, identification of a genetic mutation provided a more precise etiological cause for the patient's CKD.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Mann¹,

Braun²,

Amann³

et al. 2019

JASN

118

102

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Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroidresistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WESrelated molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

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Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Mann¹,

Braun²,

Amann³

et al. 2019

JASN

118

102

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“…6 Disruption of any of these events results in congenital anomalies of the kidney and the lower urinary tract (CAKUT); these represent 20%-30% of all anomalies identified in the prenatal period in humans. [7][8][9][10] Cell type-specific basic helix-loop-helix transcription factors are key regulators of organ morphogenesis. [11][12][13][14] Transcription factor 21 (Tcf21) (Pod1/Capsulin/Epicardin) is a class 2 basic helix-loop-helix transcription factor that shows robust expression in mesenchymal cells of the urogenital, respiratory, digestive, and cardiovascular systems throughout embryogenesis and is involved in epithelialmesenchymal interactions in the kidney, lung, and other organs.…”

Section: Discussionmentioning

confidence: 99%

“…2,[46][47][48] Importantly, mutations in RET and GDNF, as well as in other genes that regulate branching of the UB, have been associated with CAKUT. 10,42 Although a functional role of Tcf21 in human CAKUT has not yet been reported, Tcf21 has been shown to be downregulated in dysplastic fetal kidneys. 49 Here, we report a spectrum of renal developmental phenotypes that resemble human CAKUT that result from loss of Tcf21 from the germline, or from specific MM compartments.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

Ide

Finer

Maezawa

et al. 2018

JASN

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Background The mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.

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“…Aberrant embryonic kidney and urinary tract development results in a spectrum of different clinical phenotypes, which are collectively referred to as congenital anomalies of the kidney and urinary tract (CAKUT) (1)(2)(3). The spatiotemporal character of molecular disturbances is hypothesized to define the kidney and urinary tract defects of individuals (4) because early embryonic maldevelopment leads to kidney parenchyma malformations, whereas later interferences underlie ureteral anomalies (5).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, early-phase identification of patients who will develop CKD often remains problematic (15)(16)(17). Recent advancements of genetics and bioinformatics have completely revolutionized the field of medical genetics and now offer opportunities for development of clinical frameworks in genetic kidney diseases such as CAKUT (2,18). In this review, we discuss how these genetic diagnostic methods are currently integrated in the care for patients with CAKUT, and how they enable future development of precision-medicine approaches for developmental kidney and urinary tract defects.…”

Section: Introductionmentioning

confidence: 99%

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract

Westland

Renkema

Knoers

2020

CJASN

Self Cite

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Revolutions in genetics, epigenetics, and bioinformatics are currently changing the outline of diagnostics and clinical medicine. From a nephrologist's perspective, individuals with congenital anomalies of the kidney and urinary tract (CAKUT) are an important patient category: not only is CAKUT the predominant cause of kidney failure in children and young adults, but the strong phenotypic and genotypic heterogeneity of kidney and urinary tract malformations has hampered standardization of clinical decision making until now. However, patients with CAKUT may benefit from precision medicine, including an integrated diagnostics trajectory, genetic counseling, and personalized management to improve clinical outcomes of developmental kidney and urinary tract defects. In this review, we discuss the present understanding of the molecular etiology of CAKUT and the currently available genome diagnostic modalities in the clinical care of patients with CAKUT. Finally, we discuss how clinical integration of findings from large-scale genetic, epigenetic, and gene-environment interaction studies may improve the prognosis of all individuals with CAKUT.

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Genetic basis of human congenital anomalies of the kidney and urinary tract

Cited by 103 publications

References 166 publications

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract

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