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Diverse Chronic Kidney Disease Diagnoses Made With Exome Sequencing

Correction: This story has been updated with regard to the number of monogenic kidney conditions identified in single individuals. An earlier version erroneously stated that one individual carried many monogenic conditions.

NEW YORK (GenomeWeb) – Exome sequencing shows promise for diagnosing a significant subset of chronic kidney disease cases, according to new research by a Columbia University-led team.

"Our findings support the diagnostic utility of exome sequencing across different clinical categories of kidney disease and highlight the potential of genetic testing to accurately direct patients to relevant clinical trials and targeted therapies, encouraging similar investigations across other sub-specialties," corresponding author Ali Gharavi, a nephrology researcher at Columbia, and his colleagues wrote in their study online today in the New England Journal of Medicine.

The researchers did exome sequencing on two groups of chronic kidney disease patients, representing more than 3,300 individuals in all. In combination with their diagnostic analyses, the exomes yielded variants with diagnostic significance in 307 cases, including 39 monogenic conditions found in individual patients.

Including conditions represented in those individuals, the team detected 66 monogenic disorders ranging from congenital renal diseases to "nephrology of unknown origin." Within a subset of 2,187 patients treated at the Columbia University Medical Center with family history and other clinical information available, meanwhile, the analysis revealed unrelated but medically actionable variants in American College of Medical Genetics and Genomics-actionable genes in 34 individuals.

"For several patients, the information we received from DNA testing changed our clinical strategy, as each one of these genetic diagnoses comes with its own set of potential complications that must be carefully considered when selecting treatments," Gharavi said in a statement.

Studies so far suggest that the diagnostic yields that can be attained with exome sequencing fluctuate depending on the clinical condition at hand and the population being considered, the team explained, prompting a more detailed look at the diagnoses that can be obtained by profiling a range of chronic kidney disease cases with exome sequences.

"There are multiple genetic causes of chronic kidney disease, and treatment can vary depending on the cause," Gharavi said. "But many of the genetic types are rare and can be difficult to detect with traditional diagnostics."

With that in mind, he and his colleagues used Illumina instruments to sequence protein-coding sequences captured with Roche or Integrated DNA Technologies kits from 3,315 individuals with chronic kidney disease. Of those, they noted, 281 cases had previously been classified as nephrology of unknown origin.

Among the 307 patients diagnosed with the help of exome sequence data, the team saw 206 autosomal dominant disease cases, 42 individuals with autosomal recessive disease, 54 X-linked conditions, and five individuals with more than one molecular diagnosis. The proportion of cases diagnosed with exome sequences notched up in the cases not diagnosed previously with standard clinical testing. There, the exome sequences led to molecular diagnoses in 48 (more than 17 percent) of those cases.

Another 18 patients had their diagnoses refined with the new genetic data, the researchers reported, while secondary findings in non-kidney disease-related genes — including immunosuppression-related genes — informed the types of treatments provided for still more individuals with chronic kidney disease.

"Our study shows that genetic testing can be used to personalize the diagnosis and management of kidney disease," Gharavi said, "and that nephrologists should consider incorporating it into the diagnostic workup for these patients."

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