About 10 percent of kids born with kidney defects have alterations in their genomes known to be linked with neurodevelopmental delays and mental illness, according to a new study. Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the U.S. and are present in about 1 in every 200 births. There is thus about a .05 percent chance that a newborn will have kidney defects and these disorders.
Researchers at Columbia University Medical Center predict that an evaluation for genomic alterations will eventually be part of the standard clinical workup. Patients with congenital kidney disease — who are currently lumped into one category — will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis, according to the researchers. “This changes the way we should handle these kids,” said kidney specialist Ali Gharavi, M.D., associate professor of medicine at Columbia University Medical Center, associate director of the Division of Nephrology, and an internist and nephrologist at New York-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.” “This is a major opportunity for personalizing medical care,” he continued. “As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.”
The study was the result of a large collaborative effort of researchers at Columbia University Medical Center and other medical centers in the U.S., Italy, Poland, Croatia, Macedonia, and the Czech Republic. Until now, there haven’t been any studies linking congenital kidney disease with neurodevelopmental disorders. But doctors have seen the association, according to the researchers. “If you talk to clinicians, they tell you that some of these kids behave differently,” said Dr. Simone Sanna-Cherchi, an associate research scientist in CUMC’s Department of Medicine. “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.”
The mutations discovered by Gharavi and Sanna-Cherchi and their colleagues are called copy number variations (CNVs), which 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, the researchers explain. Until the mid-2000s, when techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders, including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, 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, according to the researchers.
It is unclear why kidney malformations and neurodevelopment are linked, but it is possible that the same genes involved in kidney development are involved in brain development, Gharavi speculated. The search for CNVs in congenital kidney disease also showed that the genes involved in the disease are far more numerous than anticipated, he added. “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,” he said. “Virtually every patient has a unique condition that could not be diagnosed by a standard clinical evaluation.” Based on these results, Gharavi and Sanna-Cherchi estimate that there may be hundreds of different genes that can lead to congenital kidney malformation. The study was published in the online edition of the American Journal of Human Genetics.