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Genetic sequencing may advise diagnosis, management of CKD

Whole-exome sequencing, which analyzes DNA from the protein-coding part of the genome, helped identify the genetic cause of kidney disease and inform treatment in adults with chronic kidney disease, according to pilot study results published in Annals of Internal Medicine.

“Next-generation sequencing has been shown to have great utility for diagnosing genetic forms of nephrotic syndrome or congenital kidney defects in pediatric populations. [Whole-exome sequencing] is emerging as a preferred diagnostic tool for hereditary disorders,” Sneh Lata, PhD, from Columbia University, and colleagues wrote. “However, the value of this sequencing method for the diagnosis and management of CKD in adults has not been adequately studied.”

The cause of kidney failure in adults with CKD is often unclear; however, genetic diagnostics may be beneficial to this population. Therefore, in this observational pilot study, researchers examined the diagnostic utility of whole-exome sequencing in 92 adult patients from Colombia University Medical Center with CKD of unknown cause, or familial nephropathy or hypertension. They measured the diagnostic yield of whole-exome sequencing and its possible impact on clinical management.

Whole-exome sequencing yielded a diagnosis in 22 of 92 participants (24%), including 9 probands with CKD of unknown cause and 13 different genetic disorders. Of these 9 patients with unknown cause of kidney failure, whole-exome sequencing clarified the clinical diagnosis or reclassified the patient’s disease, which significantly impacted clinical management. These findings affected the clinicians’ initiation of targeted surveillance, familial screening to steer donor selection for transplantation and changes in CKD treatment.

Further, whole-exome sequencing identified PARN haploinsufficiency as a new genetic cause of CKD, according to Lata and colleagues. In two probands with fibrosis, sequencing identified loss-of-function mutations in PARN. Additionally, examination of the American College of Medical Genetics actionable genes revealed a pathogenic BRCA2 mutation in a proband who was diagnosed in follow-up with breast cancer.

“In this study, [whole-exome sequencing] had substantial diagnostic yield and affected clinical management in a referral population of adults with CKD, inviting more extensive investigation of the broader clinical utility of genetic testing for the CKD population,” Lata and colleagues wrote.

“Altogether, [whole-exome sequencing] offers the advantage of screening most relevant nephropathy genes at once, providing genetic diagnoses across diverse clinical categories, and enabling the identification of novel phenotypic extensions, as shown by the findings of PARN mutations in tubulointerstitial nephropathy,” they continued. “Because of its genome-wide approach, [whole-exome sequencing] also enables periodic reevaluation of the sequence data for new genetic diagnoses as new disease genes are identified.” – by Savannah Demko

Disclosures: Lata reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.