Evolution of Genetics, Genetic Testing, and Genotype Predictor Scores for Hypertrophic Cardiomyopathy: Phenotype Is Still King

Having reached the 35th anniversary since the discovery of the first disease‐causative gene and mutation for hypertrophic cardiomyopathy (HCM) this year, it is a great time to look back with amazement at the large number of discoveries made in the world of genetic HCM and the speed at which they have been made. Since the discovery of HCM‐causative pathogenic variants in the MYH7‐encoded beta myosin heavy chain, ¹ hundreds of mutations in >20 genes have been associated with the pathogenesis of HCM. Over the same time, gene and mutation discovery research has progressed from cumbersome single gene sequencing methods to ultrafast next generation sequencing techniques, clinically informative genotype–phenotype correlations continue to be described, and artificial intelligence algorithms are being developed and implemented to help with diagnosis and management in real time. And—most recently—after decades of using “off‐label” medications for the treatment of HCM‐associated symptoms, we now have a Food and Drug Administration‐approved drug, a cardiac myosin inhibitor, with an indication for the treatment of patients with symptomatic, obstructive HCM. In addition, genotype‐specific gene therapy trials have begun in humans. As such, the genomic era of medicine has truly arrived for HCM emphasizing a true necessity for genetic testing in every patient and their family to identify their genetic marker and personalize treatment and management accordingly.

Yet, despite genetic testing being recommended for probands with HCM in the most recent American Heart Association/American College of Cardiolgoy guidelines (Class 1B), ² several hurdles, such as availability of testing, insurance coverage, patient and family hesitance, and delays in and challenges of interpretation of genetic test results complicate direct usage in clinical practice. To this end, we previously developed the Mayo Clinic genotype predictor score, a set of 6 easy‐to‐assess clinical markers associated with genotype positive status, that, when combined, predicted the likelihood of a positive genetic test for sarcomeric HCM ³ ; a similar score was published by a group in Toronto around the same time. ⁴ Over the past decade, both scores have been validated and tested in various studies, cementing the clinical role of these genotype predictor scores. In addition, as genetic testing has become commonplace in the workup of HCM and early artificial intelligence algorithms are starting to show promise in aiding the decision process, a multicenter study by Hiruma et al. in this issue of the Journal of the American Heart Association (JAHA) ⁵ shows there is still room for easy‐to‐use scores like the Mayo score with the addition of ECG parameters to further enhance its performance. Following the same strategy we used in its development over a decade ago, Hiruma et al. conducted an extensive ECG evaluation demonstrating that genotype positive patients more often exhibited atrial fibrillation and intraventricular conduction disturbances and had lower prevalence of high voltage and T‐wave inversion when compared with genotype negative patients. ⁵ Not only are these important findings by themselves, highlighting critical electromechanical differences between genotype positive and genotype negative patients, adding these ECG phenotypes to the Mayo HCM score to create an ECG‐enhanced Mayo score (+1 point for AF, +1 point for intraventricular conduction disturbance, −1 for low voltage, −1 for abnormal T‐waves), showed increased performance over the Mayo score (area under the receiver operating characteristic curve 0.81 versus 0.76; P=0.005). This new score now stratified genotype positivity from 7.1% (score≤−1) to >90% (score≥4) providing excellent pretest probability of a positive genetic test for (sarcomeric) HCM.

But the genotype–phenotype correlations and ECG‐enhanced Mayo score presented herein not only offers a new score with better performance, it also highlights something far more crucial: phenotype matters! Despite all genomic, technological and artificial intelligence advances, it is the patient in front of you, their story and past medical history, and the results of set of clinically indicated diagnostic tests for the diagnosis of HCM that yields a simple score and provides crucial, on‐the‐spot crucial guidance on whether to pursue genetic testing. Furthermore, it can facilitate the start of important genetic counseling conversations for your patient and their family members. Lastly, it sets the stage for important treatment decisions that are, as previously discussed, become increasingly personalized and genotype‐oriented. But phenotype is not crucial in the diagnostic process alone. In fact, we and others have long stressed that phenotype is equally important in the interpretation of genetic test results, especially when it comes to the adjudication of variants of uncertain significance. Although the 2015 American College of Medical Genetics and Genomics guidelines for the interpretation of genetic variants provides a framework to adjudicate genetic test results, ⁶ a patient’s phenotype was considered trivially in the final score, despite a large body of literature showing clear genotype–phenotype correlations among various genetic heart diseases. Building on these observations, numerous studies have demonstrated the power of the phenotype to enhance the American College of Medical Genetics and Genomics framework and in the process elevated many variants of uncertain significance to (likely) pathogenic thereby improving management and treatment of families with a genotype positive genetic heart disease. ⁷ , ⁸ , ⁹ This work now comes full circle, as Hiruma et al. show their enhanced ECG‐Mayo score remains a powerful tool when variants of uncertain significance are included in testing of their model. ⁵

Lastly, the importance of phenotype is not just highlighted by their role in the performance of the novel Mayo ECG score, their detailed genotype–phenotype and long‐term outcome analyses yet again validate that—akin to prior studies ¹⁰ , ¹¹ —genotype positive patients are significantly more likely to experience a arrhythmic event (log‐rank P<0.001) or deteriorate to heart failure (log‐rank P<0.001). Altogether these data, along with the development of an enhanced, yet easy‐to‐use genotype predictor score reemphasize the importance of straightforward, but carefully developed genotype–phenotype studies in HCM as presented elegantly herein by Hiruma et al. ⁵ Although technology and artificial intelligence may provide fast and novel insights in diagnosis and management of disease, a simple assessment of your patient’s phenotype remains invaluable to provide the best care.

Disclosures

J. Martijn Bos and Michael J. Ackerman are supported by the Mayo Clinic Windland Smith Rice Sudden Cardiac Death Program.