Bigger isn’t better: A lesson learned from genes of uncertain significance
Julie Hathaway · Oct 12, 2018

While rapid advances in diagnostic technology have broadened the testing options available to clinicians, this has come at the cost of increasing uncertainty. Genes of uncertain significance (GUS) continue to be included on cardiovascular genetics testing panels despite the lack of evidence supporting their gene-disease association.

Genetic testing in cardiovascular disease has become an important and recommended part of a patient’s diagnostic work-up.1 Results may have implications for the patient’s medical management and may be the only way to identify family members who are at risk for sudden death.

To be able to clearly communicate what the findings mean to the patient and their families, it is essential to understand the evidence behind the genes in which variants were found.

What is a gene of uncertain significance? Let’s start with a few trends and take a look at the rapid development of the genetic testing landscape in numbers.

The number of genes associated with inherited arrhythmias and cardiomyopathies has increased significantly over the last three decades.  In the mid-1990s, the first Hypertrophic Cardiomyopathy (HCM) gene was described and now, the average commercially available genetic testing panel contains approximately 40 genes, sometimes as many as 60.  The first three Long QT syndrome genes were also described in the 1990s; in 2018, 16 genes are routinely analyzed for this indication. Perhaps most impressive has been the creation of all-encompassing broad panels containing over 100 genes to accommodate overlapping and/or unclear phenotypes.

Why did the size of gene panels grow so quickly? The arrival of next generation sequencing (NGS) technology in the mid-2000s has certainly had an impact; this new testing method makes it relatively simple and inexpensive to update panels. New genes reported to be associated with inherited cardiac conditions in published case reports and small cohort studies could be readily incorporated into diagnostic panels. At the same time, NGS technology was also being used to compile extensive data on naturally occurring genetic variation in the general population.

As population and clinical data accumulated, it soon became apparent that an increase in the number of genes added to a testing panel did not improve the diagnostic yield, but rather resulted in an increase in variants of uncertain significance.

For example, of the >600 HCM index patients tested for 18-51 genes, only one was found to have a likely pathogenic/pathogenic variant in a gene outside of the original “core” 11 HCM genes. Further, approximately 80% of positive genetic test results were variants in the genes first discovered to be associated with HCM; MYH7 and MYBPC3.2 Similarly, for LQTS, the greatest majority of all cases continue to be explained by variants in the genes first described in this condition; KCNQ1, KCNH2 and SCN5A.3

Both the publication of more stringent variant classification criteria in 20154 and population data lead to the scrutiny of reported disease-causing variants in some of the “newer genes” added to testing panels. In many cases, no segregation data or adequate functional data was available and many ‘disease-causing’ variants were found to be common in the general population. ANKRD1 (HCM) and SNTA1 (LQTS) are two examples that readily come to mind. As a result, the lack of very compelling disease-causing variants in these new genes weakens their causal association with inherited arrhythmia or cardiomyopathy.  Just like the variants reported within them, these genes may also be considered of “uncertain significance”.

Genes of uncertain significance create important challenges in clinical work. Variants in these genes may be subject to reclassification, leaving the clinician with the difficult task of communicating not only this new interpretation, but also the resulting clinical implications, to families.  Many of us who have worked in this area for some time can likely remember being in this very situation; maybe even more than once.

If genes of uncertain significance are only going to raise more questions and create difficult situations, then we should reconsider our reasoning behind panel composition. If bigger isn’t better and won’t bring more answers, our focus should not be on size, but instead on the clinical relevance of what is being offered.

Coming up next: Resources that shed light on genes of uncertain significance


Julie Hathaway
Clinical Liaison

Julie Hathaway is a Clinical Liaison at Blueprint Genetics. She has several years’ experience working in cardiac genetics; her past roles include both program coordinator and genetic counselor in a provincial multidisciplinary inherited arrhythmia program. Julie is an American and Canadian Board Certified Genetic counselor.


Morales, A., Hershberger, R. Clinical Application of Genetic Testing in Heart Failure. Curr Heart Fail Rep 14, 543–553 (2017).

Alfares, A., Kelly, M., McDermott, G. et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med 17, 880–888 (2015). 

Hedley, P.L., Jørgensen, P., Schlamowitz, S., et al. (2009), The genetic basis of long QT and short QT syndromes: A mutation update. Hum. Mutat., 30: 1486-1511.

Richards, S., Aziz, N., Bale, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–423 (2015).

Last modified: October 27, 2020