Genome Analysis Can Overestimate Incidence of Chronic Kidney Disease

MedicalResearch.com Interview with:

Hila Milo Rasoul, PhD Postdoctoral research scientist Ali Gharavi Lab Columbia University

Dr. Milo Rasouly

Hila Milo Rasouly, PhD
Postdoctoral research scientist
Ali Gharavi Lab
Columbia University

MedicalResearch.com: What is the background for this study?

Response: Genome sequencing is increasingly used in clinical medicine to help make a clinical diagnosis and make predictions about potential future complications. The diagnostic yield and limitations for different indications are still being worked out.  We are interested in studying the applications of genome sequencing for chronic kidney diseases. It is estimated that 10% of adults have chronic kidney disease (CKD), and amongst them, 10% are caused by single-gene (Mendelian) forms of disease.

The American College of Medical Genetics and Genomics developed guidelines on how to interpret genetic variants in order to make a genetic diagnosis. Our lab has been engaged in studying the yield and impact of genetic testing for  CKD, and in the course of our research, we realized that a very large number of individuals have genetic variants that may be classified as pathogenic based on automated application of the guidelines. However, in majority of these cases, the genetic variant was much too frequent in the population to be plausibly disease-causing or did not match up well with the clinical diagnosis. This led us to wonder about the risk of false-positive genetic diagnosis. To analyze this risk for false-positive genetic diagnosis, we analyzed the genome sequence of 7,974 self-reported healthy adults.

MedicalResearch.com: What are the main findings?

 Response: The main finding of the study is that if one utilizes automated application of guidelines, up to 23% of healthy individuals would be classified as having a sequence variant suspicious for genetic kidney disease, which would be higher than the prevalence of CKD itself. This is obviously not plausible.

Most candidate genetic diagnosis originated from old reports of pathogenic variants but with new data available, we know that most of these variants are too frequent in the population to be truly disease-causing. Such variants are still catalogued as disease-causing in databases commonly used by geneticists to annotate sequencing results, potentially leading to misclassification.

Even with much more stringent data analysis, we were still left with 1.3% of healthy persons with a sequence variant suspicious for a genetic kidney disease. This indicated that  further diagnostic tests would be required to refute or confirm such candidate genetic diagnoses, potentially initiating many “diagnostic odysseys”, especially in the context of reporting of incidental findings in an otherwise healthy individual.

MedicalResearch.com: What should readers take away from your report?

Response: Like any other test, genetic test results have their limitations. This research illustrates that we can use sequencing to determine whether someone with a clinical diagnosis of CKD has a genetic form of disease, but we still have a lot of work to do before we can make a prediction of genetic kidney disease in an otherwise healthy individual.  While our genetic makeup doesn’t change over time,  the classification of variants may change. In other words, our understanding of the clinical impact of genetic variants does change as data accumulate. Therefore, clinicians should always use the most updated genetic information and always interpret genetic results in the context of clinical information.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Like any other test, genetic test results have their limitations. This research illustrates that we can use sequencing to determine whether someone with a clinical diagnosis of CKD has a genetic form of disease, but we still have a lot of work to do before we can make a prediction of genetic kidney disease in an otherwise healthy individual.  While our genetic makeup doesn’t change over time,  the classification of variants may change. In other words, our understanding of the clinical impact of genetic variants does change as data accumulate. Therefore, clinicians should always use the most updated genetic information and always interpret genetic results in the context of clinical information.

MedicalResearch.com: Is there anything else you would like to add?

Response: Genetic diagnosis can be extremely helpful for patients, and this paper should NOT prevent anyone from offering genetic testing to their patients. Genetics, like any other field in medicine, has its limitations, and we should simply be aware of them.

We tried to make this paper as accessible as possible, with a comprehensive glossary to help anyone not familiar with genetics better understand the process, and the limitations of genetic analysis. We hope it will help better serve all patients

Citation:

Rasouly HM, Groopman EE, Heyman-Kantor R, Fasel DA, Mitrotti A, Westland R, et al. The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing. Ann Intern Med. [Epub ahead of print ] doi: 10.7326/M18-1241

Nov 27, 2018 @ 7:05 pm 

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