The Role of Genomics in Pediatric Kidney Disease Management

In the United States, the most common diagnostic group of chronic kidney disease(CKD) that manifests before age 25 is congenital anomalies of the kidneys and urinary tract (CAKUT) (49.1%). One study suggested that early onset CKD is caused by mutations in any one of more than 200 different monogenic genes.¹

Children’s Mercy Kansas City, recognized as one of the top 10 pediatric nephrology programs in the nation by U.S. News & World Report, is also one of the few to feature a physician with dual expertise in nephrology and genomics. Here, Laurel K. Willig, MD, Pediatric Nephrologist and Medical Director, Genomic Medicine Center, highlights the important role of genomics in the diagnosis, treatment and management of pediatric kidney disease.

Q. HOW IMPORTANT IS GENOME SEQUENCING TO THE DIAGNOSIS AND TREATMENT OF PEDIATRIC KIDNEY DISEASE TODAY?

A. From a clinical perspective, a decade ago most people would have said there’s no reason to do genetic testing on many of these patients. We knew what the diagnosis was, and the results didn’t change the therapy. But, as the cost of sequencing has gone down and genomic technology has become more accessible, it’s becoming much more widely used to confirm inherited nephrology conditions such as polycystic kidney disease (PKD), Alport syndrome and tuberoussclerosis, among others.

Q. WHAT DIFFERENCE DOES SEQUENCING MAKE? HOW IS IT HELPFUL?

A. Genomics and epigenomics can potentially provide patients and families with answers to their diagnostic odyssey. These tests also empower families who are dealing with lifelong disease processes by providing them with informationregarding the type of genetic change they have,their prognosis and potential therapies for certain diseases that can be clinically diagnosed. For example, genetic testing for hereditary glomerulonephritis may allow families to avoid more invasive diagnostic procedures such as renal biopsy. This could also provide important prognostic information as there are dominant, recessive or X-linked forms that may vary, especially in females, in terms of the risk for progression to kidney failure and the development of extra renal manifestations. Recently, newer genotype/phenotype prediction programs have been developed to predict disease severity and also potentially clarify which mutations are likely to be benign.² Finally, researchers have employed exon skipping in mice to help preserve kidney function in those mice with certain types of genetic mutations. This may be on the horizon for certain patients, but they must undergo genetic testing to make this possible.

Q. WHAT TYPES OF GENOMIC TESTS ARE YOU DOING FOR PEDIATRIC NEPHROLOGY? CAN EXTERNAL SITES/PROVIDERS REFER FOR TESTING?

A. Our genome center, which is integrated into thehospital, offers a wide variety of CLIA-certified testing,including microarrays, single and small custom next generation sequencing gene panels, whole exome sequencing and whole genome sequencing. This sequencing can be ordered with additional testing for copy number variation if indicated. We also offer parental testing when indicated for certain scenarios. All clinical testing can be ordered by providers outside Children’s Mercy.

Q. HOW DO YOU INCORPORATE GENOMIC SEQUENCING INTO CLINICAL CARE?

A. Our Pediatric Nephrology Genetics Clinic is a consultative clinic that centralizes care for patients with known genetic disorders that require renal surveillance and follow-up. Currently, we see about 50 to 60 patients per year as part of this clinic, including new patients and those receiving ongoing follow-up. My goal is to incorporate genetic testing into the clinical care model for nephrology patients, helping identify and treat more children with inherited kidney diseases. I believe that a molecular genetic diagnosis, even in the case of a clinically diagnosable disease, is and will become more important for both prognostication and treatment.There are already ongoing trials of treatment options that target only specific types of genetic mutations that lead to the same clinical disease entity. Finally, I try to stay current on the research opportunities for both rare and common genetic kidney diseases, and share information with families when applicable, empowering them to take part in new research if they wish.

Q. HOW DOES THE CLINIC WORK?

A. We systematically utilize genetic testing available through the Children’s Mercy Genomic Medicine Center to diagnose genetic forms of CKD, such as Alport syndrome, tuberous sclerosis, tubulopathies, hereditary hemolytic uremic syndrome, nephrotic syndrome and polycystic kidney disease (PKD). A dedicated genetic counselor is also a valuable team member who consults with each family. The genetic testing we perform allows us to make amore specific diagnosis. With this information, we can monitor and institute early treatment related to other biologic processes that are taking place in association with genetic forms of CKD to achieve the best possible patient outcomes. We also have subspecialty clinics where we see patients with inherited kidney diseases, including cystinosis, tuberous sclerosis and Beckwith-Wiedemann syndrome.

Q. WHAT HAPPENS IF YOU CAN’T PINPOINT A CLINICAL GENETIC DIAGNOSIS THROUGH TRADITIONAL TESTING?

A. Sometimes the genetic testing results families receive aren’t definitive — the answer may lie in a“blind spot” that either we cannot test for with current technology or we don’t know enough about our genomes to understand what the difference means. At Children’s Mercy, we have a unique rare diseases initiative from the Children’s Mercy Research Institute and the Genomic Medicine Center called Genomic Answers for Kids. This hospitalwide genomic research study systematically employs third-generation sequencing and single-cell genomics to uncover more inherited mutations in patients with rare diseases.Ultimately, the program will collect rare disease genomic data and health information from 30,000 children and their families over the next seven years, creating a database of nearly 100,000 genomes. Patients who have undergone appropriate clinical testing could potentially take part in this research if no answer pertaining to their particular disorderhas been found. This testing includes additional transcriptomic and methylation testing in some cases. We have enrolled approximately 25 nephrology patients and their families in this project. Outside physicians can contact the Children’s Mercy Genomic Medicine Center for details.

Q. WHAT RESEARCH PROJECTSIS CHILDREN’S MERCY INVOLVED IN RELATED TO KIDNEY DISEASE AND GENOMICS?

A. Children’s Mercy is a subsite, working collaboratively with the University of Kansas Medical Center, to enroll patients in an NIH-funded biorepository for autosomal dominant polycystic kidney disease (ADPKD) called the Early PKD Observational Cohort (EPOC) study. The purpose ofthe protocol is to expand and follow a longitudinal observational cohort of patients with early-stage PKD and extenda database of clinical information.We have separate funding from the Polycystic Kidney Disease Foundation to apply scRNA-seq to cystic and non-cystic areas of the porcine kidney to identify and characterize subpopulations of cells present in earlydisease, and the biologic pathways that maybe important for cyst initiation in early disease. This project is done in collaboration with Precigen Exemplar, where the pig model was developed and where the tissue is obtained, and The University of Kansas Medical Center, where some of the follow up functional studies are performed.

We also have a BioNexus grant studying the continued widespread use of DNA methylationpatterns in rs-cf DNA as a biomarker of disease severity and progression in congenital anomalies of the kidney and urinary tract. And, in a separate but related project, we are looking at a new disease immunogenomic approach for gaining insight into inflammatory complications in solid organ transplantation, and developing new noninvasive approaches to monitor complications. Finally, we as a nephrology group participate in many multicentered studies such as CKiD, CureGN and NEPTUNE, all of which incorporate genomic testing.

Q. HOW DO YOU SEE GENOMICS SHAPING THE FUTURE OF CLINICAL CARE FOR PEDIATRIC KIDNEY DISEASE PATIENTS?

A. Genetic testing is already becoming such a ubiquitous part of clinical care, it is just a matter of time before it becomes integrated into the standard work-up for pediatric kidney disease. The information this testing provides will guide us to answers for these patients and their families, and targeted, more effective therapies. Soon there may be therapies to treat cystinosis or hereditary glomerulonephritis that depend on the patient’s actual genetic changes, making testing a necessity in order to provide access to these potential groundbreaking treatments. Overall, genomic sequencing will accelerate this process for patients and families.

SOURCES

1. Vivante A, Hildebrandt F. Exome Sequencing Frequently Reveals the Cause of Early-Onset Chronic Kidney Disease. Nat Rev Nephrol. 2016 Mar;12(3):133-46. doi: 10.1038/nrneph.2015.205. Epub 2016 Jan 11.

2. Kamura M, Yamamura T, Omachi K, Suico MA, Nozu K, Kaseda S,Kuwazuru J, Shuto T, Iijima K, Kai H. Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome. KidneyInt Rep. 2020 Jan 30;5(5):718-726. doi: 10.1016/j.ekir.2020.01.008. PMID:32405592; PMCID: PMC7210609.