Negative or Inconclusive Kidney Gene Panel? When To Consider Exome Sequencing

Genetic testing has transformed the diagnosis and management of chronic kidney disease (CKD), with mounting evidence showing that inherited causes play an important role across many kidney disorders, especially in pediatric patients.

A landmark 2019 New England Journal of Medicine study found that in a cohort of more than 3,000 patients with CKD, just under 10% had a genetic diagnosis. Xiangling Wang, MD, PhD, founding director of Cleveland Clinic’s Renal Genetics Program, says this trend is even more pronounced in specialty practice.

“In our specialized clinic, 20-40% of adults and up to 70% of selected pediatric patients have a genetic cause,” she says. Growing recognition of the prevalence of genetic kidney disease has led nephrologists to use genetic testing more often.

Clarifying the role of exome sequencing in genetic kidney disease

As genetic testing becomes more common in nephrology, practical questions remain about which testing strategy offers the greatest value. Exome sequencing is often expected to yield more than panel testing because it assesses all known disease genes, Dr. Wang explains. However, it is more expensive and not always covered by insurance. Importantly, exome analysis is usually phenotype-guided, meaning the lab interprets only a subset of the sequenced genes, so real-world yields are highly phenotype- and cohort-dependent rather than uniformly superior.

To better define its role in kidney care, Dr. Wang and her colleagues asked several questions: What is the real-world value of exome sequencing after a negative or inconclusive kidney gene panel? Which patients are most likely to undergo second-tier exome sequencing, and which are most likely to receive a diagnosis from it?

They published their findings in the Clinical Journal of the American Society of Nephrology

The research team conducted a retrospective review of patients seen in the Cleveland Clinic Renal Genetics Clinic from January 2019 through June 2024. The study included 584 patients who underwent genetic testing, including 110 pediatric patients. Of those, 457 had kidney gene panel testing, 98 underwent exome sequencing and 54 had exome sequencing after a prior negative or inconclusive panel.

Exome sequencing: additional answers in 13% of cases after nondiagnostic panel testing

Overall, the diagnostic yield was 33% for kidney gene panel testing and 31% for exome sequencing, respectively. But Dr. Wang stresses that these yields in different patient groups and are not a head-to-head comparison.

She further emphasizes the key finding: among patients who underwent exome sequencing after a negative or inconclusive kidney gene panel, 13% (7 of 54) had newly identified or upgraded pathogenic findings.

For clinicians, that means a negative panel result may not be the end of the diagnostic process when suspicion for inherited kidney disease remains high.

Which patients may benefit most?

Several patterns emerged among patients who underwent exome sequencing after a nondiagnostic panel.

“The primary clinical picture reveals these are younger patients, with a family history of kidney disease and those with extrarenal manifestations, like neurologic and cardiac issues or skeletal anomalies,” Dr. Wang says.

When the researchers examined diagnostic yield by phenotype after negative panel testing, they found:

• 50% for congenital anomalies of the kidney and urinary tract
• 25% for nephrolithiasis/nephrocalcinosis
• 12.5% for glomerular disease
• 10% for cystic kidney disease
• 8% for electrolyte disorders

“These findings were interesting but also not surprising to me,” says Dr. Wang. “The data are consistent with our clinical impression when we see patients.”

In her practice, she says, she expects about half of patients with congenital anomalies of the kidney and urinary tract to receive a positive genetic diagnosis. By contrast, electrolyte disorders can remain difficult to diagnose even with exome sequencing.

That, she notes, is a reminder that exome sequencing evaluates known genes, while some disease-causing genes may still be undiscovered or not fully understood.

For example, the study highlighted a potential blind spot in current kidney genes panel testing: mitochondrial gene findings in glomerular disease. Those variants were identified through exome sequencing and may be missed on some kidney gene panels.

When to refer

The findings reinforce the value of exome sequencing when a first-tier panel test is negative or inconclusive, but clinical suspicion for genetic kidney disease remains high. Dr. Wang encourages nephrologists to trust their clinical instincts and refer these patients to a dedicated renal genetics clinic for further evaluation and specialized testing.

“We will have a chance, although it's not 100%, but based on this study, we will have a 13% chance to identify a cause that will impact the diagnosis and management for those patients,” she says.