NEW YORK (GenomeWeb) – Results from a pilot study suggest exome sequencing can lead to diagnoses in a significant proportion of chronic kidney disease cases, particularly when dealing with familial or suspected genetic maladies.
Researchers from the US, Poland, Italy, France, and the Netherlands used exome sequencing to profile samples from 92 individuals with kidney disease, including those with familial nephropathy, hypertension, and more than a dozen previously undiagnosed cases. As reported today in the Annals of Internal Medicine, they successfully diagnosed nearly one quarter of the cases based on their protein-coding DNA sequences.
Across the 22 diagnosed individuals, among them 10 with previously unexplained kidney disease, the team identified more than a dozen different genetic conditions. The group also expanded the phenotype for mutations in PARN, a gene already appreciated for its role in a short telomere syndrome.
"Our study, though small, demonstrates that whole-exome sequencing may offer real clinical value in diagnosing and managing patients with kidney disease, especially those with a family history of kidney problems or those with an unknown cause of disease," senior author Ali Gharavi, chief of Columbia University's nephrology division, said in a statement.
"Additional studies, in larger and more diverse patient populations, could help better define which categories of patients would benefit most from genomic sequencing in their clinical workup for kidney disease," he added.
Starting from 344 individuals who attended Columbia University Medical Center outpatient nephrology clinics between October 2013 and May 2014, the researchers identified 81 individuals with an apparent familial condition, undiagnosed kidney disease, a potential genetic condition, or other kidney impairments. Eleven more cases were referred from other centers.
For these 92 individuals, the team used Illumina HiSeq 2000 or 2500 instruments to sequence protein-coding DNA captured with Agilent SureSelect kits, generating 110-fold average coverage of each exome.
Of the 22 kidney disease patients who carried suspicious mutations in their exomes, the researchers identified 19 cases with pathogenic or likely pathogenic mutations in genes already implicated in kidney problems, known as nephropathy. Half a dozen of those alterations confirmed existing clinical diagnoses, while the sequence data provided new diagnoses and shored up or reclassified shakier diagnoses in 13 cases.
Those new diagnoses sometimes led to clear therapeutic strategies, the researchers explained, while cases that were reclassified could be managed more effectively. Depending on the condition, they expect the exome sequence data to hold clues about family members who may or may not be appropriate donors for those kidney disease patients requiring a transplant.
The genetic insights also provided inheritance information, helping to identify family members who may be prone to the same kidney disease or secondary findings that warrant enhanced screening.
When they evaluated the exomes with an eye for worrisome mutations in genes flagged as actionable by the American College of Medical Genetics and Genomics, the researchers identified a 68-year-old woman with a nonsense mutation in BRCA2 that was subsequently verified by Sanger sequencing. When they delved into her medical records, they found that she had been recently diagnosed with breast cancer.
Based on these results, the woman and her family were referred for additional screening, they noted, with two BRCA2 mutation-positive family members ultimately choosing to have prophylactic mastectomies. As for the kidney disease patient herself, the team noted that her BRCA2 mutation status resulted in tweaks to the type of immunosuppressive therapy she received for the condition that brought her in for testing.
The authors cautioned that the relatively high diagnostic yield for kidney disease patients included in the current study may partly reflect their focus on cases that appeared to involve familial or genetic forms of disease. Consequently, they wrote, "systematic WES analysis of larger, unselected [chronic kidney disease] cohorts will provide a better assessment of its overall diagnostic yield in nephrology practice."