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Researchers Uncover Genomic Imbalance in Children with Chronic Kidney Disease

NEW YORK (GenomeWeb) – Children with chronic kidney disease harbor an excess of large genomic imbalances, many of which might influence their clinical diagnoses or care, a Columbia University Medical Center-led team has found.

Using chromosomal microarrays, the researchers uncovered genomic imbalances in more than 7 percent of children with mild-to-moderate chronic kidney disease they studied, as they reported this week in the Journal of Clinical Investigation. Not only did these imbalances hint at the cause of patients' kidney disease, they also suggested a link between it and other disorders, including neurocognitive conditions.

"With conventional clinical findings, we often cannot determine the exact cause of CKD in children," senior author Ali Gharavi, the chief of the nephrology division at Columbia, said in a statement. "However, [using] chromosomal microarray analysis, it's possible in many cases to reach a more precise diagnosis and uncover information that can help define a patient's risk for other disorders, such as autism or diabetes."

Gharavi and his colleagues uncovered an excess of large, rare gene-disrupting CNVs among the 419 children with chronic kidney disease they studied — 37.7 percent of the 419 cases had at least one large rearrangement compared to 23.4 percent of the 5,056 controls.

A number of the CNVs found in the children with chronic kidney disease have previously been linked to known genomic disorders. Children diagnosed with renal hypodysplasia, for instance, were particularly enriched for such disorders.

The number of rearrangements linked to genomic disorders seen in controls, the researchers noted, was consistent with previous reports.

The most common genomic imbalances Gharavi and his colleagues identified among children with chronic kidney disease were 17q12 deletions, chromosome X duplications, 1q21.1 deletions or duplications, and homozygous CTNS deletions.

Deletion of 17q12, which includes the HNFI homeobox B gene, is diagnostic for renal cysts and diabetes (RCAD) syndrome, the researchers said, while homozygous deletion of CTNS is linked to cystinosis.

In addition, 35 cases harbored CNVs stretching to more than 500 kilobases in length. A number of these CNVs affected genes linked to kidney function such as FOX1, HOXD10/HOXD13, CDH19, and ERRB. These genes, the researchers said, may represent new candidate genes for kidney disease.

Just more than 3 percent of the pediatric chronic kidney disease cases had two or more rare, large CNVs, while 1 percent of the controls did, the researchers added.

Gharavi and his colleagues also investigated whether these genomic findings could influence the diagnosis or care of children with kidney disease.

For three patients diagnosed clinically with cystinosis, the genomic diagnosis supported the clinical one, but for the 28 other patients with a known or likely pathogenic genomic imbalance, the genomic diagnosis reclassified the patients' disease or included additional information that could require genetic counseling, targeted workup, or additional surveillance, the researchers said.

For example, three patients diagnosed with glomerulopathy or nonspecific nonglomerular disorder were reclassified to RCAD syndrome and nephronophthisis. Patients with RCAD, the researchers noted, often benefit from increased diabetes, hypomagnesemia, and hyperuricemia screening.

Gharavi and his colleagues also found that a number of the pathogenic genomic imbalances they uncovered in their study have been linked to developmental delay, intellectual disability, and seizure disorder.

"Our findings should change clinical practice," Gharavi said. "Routine genetic screening of kids with CKD would not only improve diagnosis, but also help identify those at risk for complications like diabetes and subclinical seizures, which benefit from early detection and treatment."

Additionally, the researchers said that this link between kidney disease and developmental delay or intellectual disability could explain why children with the disease tend to do less well in school than their classmates.