Researchers at Columbia University Medical Center have found that nearly 10 percent of children who are born with kidney defects also have large alterations in their genetic makeup.
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"This changes the way we should handle these kids," said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital."
"If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neurodevelopmental delay or mental illness later in life," he said. "This is a major opportunity for personalizing medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take."
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC''s Department of Medicine.
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A kidney stone is a solid mass made up of tiny crystals and may appear in any area of the urinary system.
A kidney stone is a solid mass made up of tiny crystals and may appear in any area of the urinary system.
"If you talk to clinicians, they tell you that some of these kids behave differently," Dr. Sanna-Cherchi said. "There has been a general assumption, though, that behavioral or cognitive issues in children with chronic illnesses such as kidney disease stem from the child''s difficulty in coping with the illness. Our study suggests that in some cases, neurodevelopmental issues may be attributable to an underlying genomic disorder, not the kidney disease."
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Increase in salt concentration in the urine results in precipitation of crystals and these lead to formation of kidney stones. Drinking a lot of water can prevent kidney stones.
Increase in salt concentration in the urine results in precipitation of crystals and these lead to formation of kidney stones. Drinking a lot of water can prevent kidney stones.
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the "dose" of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
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Ultrasound scan reveals multiple cysts and there is no function on that kidney when tested on DMSA scan. A vast majority of them resolve spontaneously.
Ultrasound scan reveals multiple cysts and there is no function on that kidney when tested on DMSA scan. A vast majority of them resolve spontaneously.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centers in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said.
Congenital kidney disease may involve hundreds of genes
The search for CNVs in congenital kidney disease also showed that the genes involved in the disease are far more numerous than anticipated.
"We thought we were going to find a few CNVs shared by many patients, but instead we found that virtually every patient with a CNV has a unique one," Dr. Gharavi said. "Virtually every patient has a unique condition that could not be diagnosed by a standard clinical evaluation."
Based on their results, Drs. Gharavi and Sanna-Cherchi estimate that there may be hundreds of different genes that can lead to congenital kidney malformation.
The other contributors are Simone Sanna-Cherchi (CUMC), Krzysztof Kiryluk (CUMC), Katelyn E Burgess (CUMC), Monica Bodria (G. Gaslini Institute, Genoa, Italy), Matthew G Sampson (University of Pennsylvania), Dexter Hadley (University of Pennsylvania), Shannon N Nees (CUMC), Miguel Verbitsky (CUMC), Brittany J Perry (CUMC), Roel Sterken (CUMC), Vladimir J Lozanovski (University Children''s Hospital, Skopje, Macedonia), Anna Materna-Kiryluk (Polish Registry of Congenital Malformations, Poznan, Poland), Cristina Barlassina (University of Milan), Akshata Kini (University of Pennsylvania), Valentina Corbani (Sant'' Andrea Hospital, La Spezia, Italy), Alba Carrea (G. Gaslini Institute, Genoa, Italy), Danio Somenzi (University of Parma), Corrado Murtas (G. Gaslini Institute, Genoa, Italy), Nadica Ristoska-Bojkovska (University Children''s Hospital, Skopje, Macedonia), Claudia Izzi (Montichiari Hospital, Italy), Beatrice Bianco (University of Parma), Marcin Zaniew1 (District Children Hospital, Szczecin, Poland), Hana Flogelova (Palacky University, Czech Republic), Patricia L Weng (CUMC), Nilgun Kacak (CUMC), Stefania Giberti (University of Parma), Maddalena Gigante (University of Foggia, Italy), Adela Arapovic (University Hospital of Split, Croatia), Kristina Drnasin (Pediatric Outpatient Clinic, Solin, Croatia), Gianluca Caridi (G. Gaslini Institute, Genoa, Italy), Simona Curioni (University of Milan), Franca Allegri (University of Parma), Anita Ammenti (University of Parma), Stefania Ferretti (Parma University Hospital), Vinicio Goj (Fatebenefratelli Hospital, Milan), Luca Bernardo (Fatebenefratelli Hospital, Milan), Vaidehi Jobanputra (CUMC), Wendy K Chung (CUMC), Richard P Lifton (Yale University), Stephan Sanders (Yale University), Matthew State (Yale University), Lorraine N Clark (CUMC), Marijan Saraga (University of Split, Croatia), Sandosh Padmanabhan (University of Glasgow), Anna F Dominiczak (University of Glasgow), Tatiana Foroud (Indiana University), Loreto Gesualdo (University of Foggia, Italy), Zoran Gucev (University Children''s Hospital, Skopje, Macedonai), Landino Allegri (University of Parma), Anna Latos-Bielenska (Polish Registry of Congenital Malformations, Poznan, Poland), Daniele Cusi (University of Milan), Francesco Scolari (Montichiari Hospital, Italy), Velibor Tasic (University Children''s Hospital, Skopje, Macedonai), Hakon Hakonarson (University of Pennsylvania), and Gian Marco Ghiggeri (G. Gaslini Institute, Genoa, Italy).
The research was supported by the NIH (R01DK080099) and the Italian Telethon Foundation (GGP08050). Researchers received other funding from: the American Heart Association (Scientist Development Grant 0930151N); the American Society of Nephrology (Carl W Gottschalk Research Scholar Grant); NIDDK (K23-DK090207); the Fondazione Malattie Renali nel Bambino; the American Society of Nephrology; the Doris Duke Charitable Foundation; the Polish Ministry of Health; NINDS (NS050487 and NS060113); and the Parkinson''s Disease Foundation.
The authors declare no financial conflicts of interest.
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