Dataset Information

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.

ABSTRACT: Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

SUBMITTER: Westland R

PROVIDER: S-EPMC4834924 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.

Westland Rik R Verbitsky Miguel M Vukojevic Katarina K Perry Brittany J BJ Fasel David A DA Zwijnenburg Petra J G PJ Bökenkamp Arend A Gille Johan J P JJ Saraga-Babic Mirna M Ghiggeri Gian Marco GM D'Agati Vivette D VD Schreuder Michiel F MF Gharavi Ali G AG van Wijk Joanna A E JA Sanna-Cherchi Simone S

Kidney international 20150909 6

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated ...[more]

PMID: 26352300

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Project description:ContextA congenital solitary functioning kidney (cSFK) is a common developmental defect that predisposes to hypertension and chronic kidney disease (CKD) as a consequence of hyperfiltration. Every urologist takes care of patients with a cSFK, since some will need lifelong urological care or will come with clinical problems or questions to an adult urologist later in life.ObjectiveWe aim to provide clear recommendations for the initial clinical management and follow-up of children with a cSFK.Evidence acquisitionPubMed and EMBASE were searched to identify relevant publications, which were combined with guidelines on related topics and expert opinion.Evidence synthesisInitially, cSFK diagnosis should be confirmed and risk factors for kidney injury should be identified using ultrasound. Although more research into early predictors of kidney injury is needed, additional congenital anomalies of the kidney or urinary tract and absence of compensatory kidney hypertrophy have repeatedly been associated with a worse prognosis. The role of voiding cystourethrography and antibiotic prophylaxis remains controversial, and is complicated by the exclusion of children with a cSFK from studies. A yearly follow-up for signs of kidney injury is recommended for children with a cSFK. As masked hypertension is prevalent, annual ambulatory blood pressure measurement should be considered. During puberty, an increasing incidence of kidney injury is seen, indicating that long-term follow-up is necessary. If signs of kidney injury are present, angiotensin converting enzyme inhibitors are the first-line drugs of choice.ConclusionsThis overview points to the urological and medical clinical aspects and long-term care guidance for children with a cSFK, who are at risk of hypertension and CKD. Monitoring for signs of kidney injury is therefore recommended throughout life. Large, prospective studies with long-term follow-up of clearly defined cohorts are still needed to facilitate more risk-based and individualized clinical management.Patient summaryMany children are born with only one functioning kidney, which could lead to kidney injury later in life. Therefore, a kidney ultrasound is made soon after birth, and other investigations may be needed as well. Urologists taking care of patients with a solitary functioning kidney should realize the long-term clinical aspects, which might need medical management.

Dataset Information

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.

Publications

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.

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