Genes Are Not Destiny

Corresponding Author

The patient discussed in this case report in this issue of JACC: Case Reports is an African American gentleman with a past medical history notable for apical hypertrophic cardiomyopathy (HCM) for more than 3 decades.¹ His electrocardiogram has classic findings for apical HCM, notably significant left ventricular hypertrophy and deep, symmetric T-wave inversions in the precordial leads (in this case, leads V₂-V₆). His echocardiogram demonstrated apical hypertrophy, as did his cardiac magnetic resonance imaging scan, which showed apical hypertrophy with significant mid-myocardial late gadolinium enhancement, consistent with an established diagnosis of apical HCM. The clinical course took a turn when genetic testing revealed a heterozygous pathogenic transthyretin (TTR) V142I variant without sarcomeric gene mutations. This case exposes a fundamental challenge that is sure to affect both general cardiologists and heart failure cardiologists: reconciling genetic testing and phenotypic presentations. As cardiovascular medicine continues to integrate genetic testing, it is crucial to ensure phenotypic presentation anchors diagnostic reasoning and allow genotypic testing to act as a complement to the clinical reasoning process.

As the authors very astutely mention, penetrance of TTR amyloid is variable. As a field, we are entering an era when genetic information may outpace clinicians’ ability to interpret testing within a clinical context. This union (or at times, disunion) of information is ripe for biases. Presence of a high-risk mutation or a genetic mutation with actionable treatment should not be used to justify immediate treatment of pathology associated with the mutation. The increasing prevalence of genetic testing will only reveal more genetic carriers and more opportunities for inappropriate management. Anchoring bias (in this case fixating on the presence of a positive genetic mutation) would inevitably result in mismanagement, which the team avoided by being methodical, affirming their clinical intuition of the presence of apical HCM. They not only ruled out the presence of TTR amyloidosis at the time of genetic testing, but plan to continue routine TTR monitoring through use of nuclear scintigraphy. Confirmation bias was luckily avoided in this case as well, as it would have been easy and, at times, natural to interpret the echocardiogram and electrocardiogram through a lens of amyloidosis. This would inevitably result in mismanagement for this patient as the TTR mutation was a bystander to the clinically relevant apical HCM. Availability bias also must be considered moving forward, as the increased recognition of TTR amyloidosis, while imperative to ensuring appropriate patients are treated, may result in overcalling the diagnosis and treating those without clinical consequences of the mutation.

The impact of advances in genetic testing and improved understanding of pathologic mutations are reshaping clinical practice, although not without consequences. Cascade screening and direct-to-consumer genetics have wildly morphed the landscape and allowed providers to intervene earlier, whether through establishing a diagnosis that was previously unknown, enrolling patients in rigorous surveillance programs, or initiating earlier and more effective targeted treatment regimens. This information is not benign, increasing the risk of oversurveillance, overimaging, radiation exposure, and premature pathologic labeling as a result of the aforementioned biases. Beyond the consequences stemming from the health care system, patients are forced to live with the psychological and clinical implications of being a “carrier,” which can equate to no clinical consequences for diseases with variable penetrance.² Screening is integral to the advancement of care, but this case illustrates the creation of diagnostic noise, the concept of unmasking genetic variants during testing that do not tie to phenotypic presentations.³

This case also illustrates integration of a staged, multimodal cardiovascular imaging approach to arrive at the appropriate diagnosis. The team utilized echocardiography, magnetic resonance imaging, and nuclear scintigraphy to reconcile discordant data. Biochemical markers, in this case genetic testing, that does not appropriately “fit” within a clinical presentation should not be dismissed as nuisance or noise but rather recognized as a diagnostic clue to better understand the entire clinical phenotype of the patient. The distinct diagnostic features of apical HCM seen on imaging paired with absence of findings on technetium pyrophosphate scan allowed the treatment team to ensure appropriate management was initiated. Moreover, imaging remains integral in future surveillance of this patient given the variable penetrance of TTR amyloidosis and unpredictable time of onset.

As genetic screening expands, clinicians are increasingly confronted with patients who carry disease-associated variants yet do not match the phenotypic presentation.⁴ This case underscores a critical principle: in cardiovascular medicine, phenotype must remain the anchor of diagnosis, not genotype. The integration of information in a sequential fashion with reliance on the physical exam and imaging modalities is fundamental in reaching the correct diagnosis. Genetic data are valuable when seeking clinical clarity, but without phenotypic anchoring, they risk misleading clinicians. It is imperative to not interpret this testing in a bubble independent from the individual patient.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.