Change is Hard: Transitioning from Phenotype-Based Practice to a Model Infused with Genetic and Genomics Knowledge

Genetics is phenotype and genotype. The goal of human genetics has always been to understand the relationship of genes to phenotype, and vice versa, the environment, which includes the local cellular- and organ-specific milieu as well as all that inside and outside that impacts an individual’s genetic and genomic expression.

But medicine, as we have known and practiced for centuries, has been based almost exclusively upon phenotype data – in antiquity data collected from what we could see, feel, hear, touch or smell. Medicine has evolved. Beyond our senses pathology and microbiology led the way during the last millennium.

For clinicians phenotyping is what we do: carefully collecting and describing the clinical features of our patients to understand their maladies. Our approaches have become highly sophisticated. For example, in cardiovascular medicine our imaging approaches, initially with still x-ray, now include high-speed digital video acquisition including computed tomography. We also use sonography, magnetic resonance imaging, positron emission tomography, and others.

But despite this remarkable ability to phenotype, we have not routinely had access to genetic or genomic information. We have been nearly fully reliant in phenotype. Even the practice of human genetics during much of the last century relied principally upon expert phenotyping of syndromic disease. Adding molecular genetic data to the practice of medical genetics, and specifically DNA sequence, only happened in the past 40 years. Even though the structure of DNA, the double helix was published in 1953, modern gene sequencing by the Sanger method only began in 1977.1 And while throughput of Sanger-based methods improved substantially, sufficient even to sequence the human genome, what has happened since 2007 is truly a revolution.

The revolution is next generation sequencing (NGS). NGS is a monumental inflection point in the history of medicine, triggered by new sequencing technology² that makes throughput much faster and cheaper. Check out the amazing 5 order of magnitude decrease in cost of sequencing one human genome! As collated by the National Human Genome Research Institute, a genome in 2016 can be sequenced for approximately $1000! NGS is transforming the practice of medicine as we have known it. Usual clinical medicine, what we know as medicine driven by phenotype information, can now add genetic and genomic information routinely into the daily evaluation and care of patients.

Open a leading medical journal and novel insights, derived from newly found genomic knowledge of disease pathogenesis, or new treatment interventions based on genomic make-up leap from the pages. Because cancer is essentially a genomic disease of loss of growth control, this has been a particularly fruitful era for new knowledge into malignancy and its genomic drivers.³

The impact of genetics and genomics for cardiovascular health and disease is also monumental. The greatest day-to-day impact, fully implementable now in the outpatient clinic, has been seen in rare variant genomics. We can now routinely define the genetic etiology of the cardiomyopathies, the channelopathies, the aortopathies, and familial hypercholesterolemia. Genomics is also revealing new genes and new pathways for treatment of complex genetics such as coronary artery disease.⁴ The rapidly emerging practice of cardiovascular pharmacogenomics will also become routinely integrated into care. Cardiovascular genetics and genomics clinics are springing up in major medical centers and beyond. The times they are a changing!

But change is hard. Rare variant cardiovascular genetic practice requires a shift in the perspective of the clinician, that is, how one actually views a patient in front of you. This transition in perspective is perhaps the single most fundamental aspect, at least for the practice of Mendelian or rare variant genomics, of what we need to change: we need to see the patient in front of us not only as an individual but as a proband, the first member of a family afflicted with the condition for which we need to provide care. We need to begin to imagine and understand disease based upon the family unit, not just one patient. The rest of genetic medicine follows. In addition to the medical history, taking an informed and complete family history is key, as well as understanding the role and implementing genetic counseling and genetic testing, and returning credible and useful genetic information not only for your patient but integrated for the proband’s extended family.

The problem is that most cardiovascular experts, exquisitely trained and fully attentive and dedicated to the phenotyping aspects of cardiovascular medicine, have been only minimally equipped to understand and implement genetic and genomic knowledge into practice. How will we move ahead?

Led by Dr Mital and assisted by a distinguished writing group, we are now offered an American Heart Association Scientific Statement⁵ crafted to help us understand what we need to know, how to enhance our cardiovascular genetic and genomic literacy, and what our competencies need to be. As for all of medicine, knowledge is a prerequisite, but more than knowledge we need to know how to do it. This document is a comprehensive review of all of that and more.

As summarized in the conclusion of the document, this is an exciting time for cardiovascular genetics and genomics! From the President’s Precision Medicine Initiative (PMI),⁶ the Veterans Administration Million Veteran Program, the National Heart Lung and Blood Institute’s TOPMED program, and many others, we will implement this new genetics and genomics approach into the practice of cardiovascular medicine.