Genomic imbalances in pediatric patients with chronic kidney disease

Verbitsky, Miguel; Sanna‐Cherchi, Simone; Fasel, David; Levy, Brynn; Kiryluk, Krzysztof; Wuttke, Matthias; Abraham, Alison G.; Kaskel, Frederick J.; Köttgen, Anna; Warady, Bradley A.; Furth, Susan L.; Wong, Craig S.; Gharavi, Ali G.

doi:10.1172/jci80877

Cited by 70 publications

(87 citation statements)

References 38 publications

(61 reference statements)

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“…Applying chromosomal microarray analysis, we recently showed that 7.4% of 419 children with various forms of CKD had a major known pathogenic genomic imbalance that was not suspected after clinical assessment (18). These disorders were evenly distributed among patients clinically diagnosed with congenital and noncongenital forms of CKD, indicating that genetic analysis has utility across broad clinical categories.…”

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confidence: 99%

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

et al. 2017

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Background The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown. Objective To study the diagnostic utility of WES in a selected referral population of adults with CKD. Design Observational cohort. Setting A major academic medical center. Patients 92 adults with CKD of unknown cause or familial nephropathy or hypertension. Measurements The diagnostic yield of WES and its potential effect on clinical management. Results Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands diagnosed respectively with tubulointerstitial fibrosis and CKD of unknown cause. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy. Limitation The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population. Conclusion Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted. Primary Funding Source New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

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Whole-Exome Sequencing in Adults With Chronic Kidney Disease

et al. 2017

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“…The most frequent genomic imbalances we detected in isolated MCDKs were the 17q12 deletion (renal cysts and diabetes syndrome, RCAD syndrome, MIM: 137920). The variable phenotypic spectrum of this deletion ranges from prenatally detected MCDK, renal cysts, hyperechogenic kidneys and renal agenesis, chronic kidney disease (CKD) in childhood, maturity‐onset diabetes of the young type 5 (MODY5, MIM: 137920), and neurophysiological disorders in adulthood. The ‘central 22q11.2 deletion’ we detected came along with a lower prevalence of CHDs than that in common 22q11.2 deletion .…”

Section: Discussionmentioning

confidence: 99%

Copy number variations in multicystic dysplastic kidney: update for prenatal diagnosis and genetic counseling

Zhu

Wang

et al. 2016

Prenat Diagn

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“…6,8,45 In a large cohort of 419 children with CKD, 3 patients showed a mutation in the HNF1B gene. 46 Other studies noted a prevalence of 9% in kidney transplant recipients with unknown primary disease (mostly CAKUT) and up to 40% in patients with the combination of renal malformations and diabetes. 16,47 Clissold et al summarized the prevalence of HNF1B mutations in nine studies in cohorts with $50 patients.…”

Section: Epidemiologymentioning

confidence: 98%

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

Verhave

Bech

Wetzels

et al. 2016

Journal of the American Society of Nephrology

125

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Hepatocyte nuclear factor 1b (HNF1b)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and renal function decline that preceded the diabetes, hence it was initially referred to as renal cysts and diabetes syndrome. However, it is now evident that many more symptoms occur, and diabetes and renal cysts are not always present. The multisystem phenotype is probably attributable to functional promiscuity of the HNF1b transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and parathyroid gland. Nephrologists might diagnose HNF1b-associated kidney disease in patients referred with a suspected diagnosis of autosomal dominant polycystic kidney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of unknown cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1b-associated kidney disease. A considerable proportion of these patients display hypomagnesemia, which sometimes mimics Gitelman syndrome. Other signs include early onset diabetes, gout and hyperparathyroidism, elevated liver enzymes, and congenital anomalies of the urogenital tract. Because many cases of this disease are probably undiagnosed, this review emphasizes the clinical manifestations of HNF1b-associated disease for the nephrologist.

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Genomic imbalances in pediatric patients with chronic kidney disease

Cited by 70 publications

References 38 publications

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

Copy number variations in multicystic dysplastic kidney: update for prenatal diagnosis and genetic counseling

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

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