Genetic Testing for Primary Glomerular Disease: Life-Changing Impact for Patients and Families

Among adults and children with primary glomerular diseases, about 14-26%[1] are due to genetic causes. But because genetic testing is not part of the routine diagnostic evaluation for primary glomerular diseases locally, patients with genetic causes are often misdiagnosed or diagnosed late.

As a clinician, Associate Professor Ng Kar Hui, Paediatrics Nephrology, Dialysis and Renal Transplantation, National University Hospital, is in a good position to change the trajectory of her patients. For example, the timely detection of coenzyme Q10 deficiency (a genetic condition) in one of her 10-year-old patients significantly delayed the deterioration of his kidney function. For another patient, her decisive recommendation for genetic testing and cascade screening enabled the family to identify Alport Syndrome as the underlying cause, and for appropriate treatment to be instituted.

Taking First Steps towards Realising Opportunities

“Yes, I can help my patients—but there are other patients in Singapore who also need help but are not getting them. Therefore, I was naturally very interested when I came to know about the Clinical Implementation Pilots (CIP) funded by PRECISE. I saw an opportunity to positively impact treatment for many more patients with primary glomerular diseases, their families and alter existing practices around genetic testing,” says A/Prof Ng.

As economic analysis is an integral component in the CIP, A/Prof Ng decided to approach Professor David Matchar, Programme in Health Services and Systems Research, Duke-NUS Medical School for a collaboration. She smiles, “I didn’t know David before this—so I sent him a cold email to arrange for a meet up. It turned out to be a very fruitful two-hour virtual discussion. Unexpectedly intensive, but it also brought clarity to what we needed to do.”

Prof Matchar recalls, “For me, I don’t remember much about the specifics of our conversation. But I definitely remember being impressed with Kar Hui, and what she wanted to achieve with the CIP. During that call, I realised for the first time how common Alport Syndrome is, and how we could significantly reduce the risk of progression to end-stage kidney disease with the use of angiotensin-converting enzyme inhibitors. And the fact that there is a gap in the current system in Singapore also reaffirmed the fact that this is a good area to focus on.”

That marked the beginning of the two-year CIP across multiple sites and involving various Co-Principal Investigators (PIs)—Associate Professor Jason Choo, Dr Lim Ru Sin, Dr Chan Gek Cher and Dr Esther Leow—and their teams.

Building Interest within the Healthcare Community

Although the utility of genetic testing in primary glomerular diseases has long been established in many international studies, it is seldom implemented in the local clinical settings. This CIP is unique in that it aims to clinically implement genetic testing in the local context, working through issues like capacity building, work processes, cost effectiveness and genetic literacy.

“This clinical implementation project for kidney disease is the first of its kind in Singapore. Its extensive scope meant that we had to get in touch and speak to geneticists, bioinformaticians, paediatricians, adult nephrologists, clinic managers, hospital laboratory staff, scientists—pretty much everyone. Because of this, we generated strong interest in genetics amongst the kidney specialist doctors. This is an achievement for us,” A/Prof Ng says. “However, we are also mindful that this gain can quickly be lost if it is not sustainable and scalable.”

Prof Matchar says, “That’s right—it goes beyond talking to people to keep the conversation going. We need to ensure that genetic testing is accessible. That translates into having sufficient genetic experts such as genetic counsellors and clinicians familiar with genetics. In addition, workflows surrounding patient education, referrals and consent have to be streamlined to reduce manpower costs.”

A/Prof Ng elaborates, “Then there is the need to have local accredited genetic testing laboratories. Local laboratories will allow faster turnaround time for test results, ideally around two weeks. In glomerular diseases, a timely genetic result is essential for clinical management to be altered in time—whether it is avoiding invasive procedures like kidney biopsy or starting targeted treatment strategies such as more aggressive immunosuppressants for the non-genetic cases. Genetic conditions generally do not respond well to immunosuppression. But without genetic results, doctors will empirically start aggressive immunosuppression as a trial of treatment.” Prof Matchar carries on, “If I may add, we can also look to cost savings while avoiding detrimental side effects of immunosuppressants like infections, malignancy and infertility.” 

Prof Matchar continues, “There is a silver lining to all the work that we are currently doing. We may be laying the foundation for genetic testing for primary glomerular disease—but let’s not forget that there are many other diseases that could also benefit from genetic testing. And the infrastructure that we are establishing now will be the prototype for these other diseases.”

Advocating Genetic Testing among Patients and their Families

The lack of a standard workflow is one of the reasons why genetic testing is not commonly or consistently offered to patients with primary glomerular disease. However, when it is offered to patients, they are not always receptive too. A/Prof Ng explains, “Cost is one key consideration for patients. This goes beyond the immediate cost of genetic testing—they are also concerned that the test results may affect their insurability, and ultimately, the burden of future medical costs.”

A/Prof Ng continues, “With this CIP, we hope to find solutions to these challenges as well as show solid evidence that genetic testing can be a good diagnostic tool for selected primary glomerular diseases. With early diagnosis and prompt treatment, the onset of late-stage kidney disease needing dialysis or transplant can be delayed by as much as two to four decades.”

“In the bigger context, we are thinking ahead to explore how we can add to the genetic testing services, like chatbots, educational videos, etc.,” adds A/Prof Ng. “Today, we are building an ecosystem for our future generations of nephrologists and patients.”

Click here to read more about how A/Prof Ng and Prof Matchar makes sense and cents of precision medicine in the fight against kidney failures. 

This project is supported by the National Research Foundation, Singapore, through the Singapore Ministry of Health’s National Medical Research Council and the Precision Health Research, Singapore (PRECISE), under PRECISE’s Clinical Implementation Pilot grant scheme.

[1] Connaughton DM, Hildebrandt F. Personalized medicine in chronic kidney disease by detection of monogenic mutations. Nephrol Dial Transplant. Mar 1 2020;35(3):390-397. doi:10.1093/ndt/gfz028