The Impact of Molecular Autopsy for Cardiac Genetic Conditions

Nori Williams, MS, CGC

A recent multicenter study out of Spain by Ripoll-Vera et al. entitled “Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing” investigates the utility of molecular autopsy. A sudden death is one that carries with it an extended grief tied to the incomprehensible fact that someone can die without warning or the knowledge of how and why. A proportion of sudden deaths are caused by a genetic cardiac condition that the person simply did not know they had. These conditions are scary because the first sign can be sudden death, but they are treatable if you know you have them. This knowledge is why post mortem genetic diagnosis, also known as molecular autopsy, is an invaluable tool. Since we share our genes with our families, that risk can be passed to family members left behind after the sudden loss of a loved one. Through post mortem genetic testing, once a diagnosis is made, individuals and families can harness that power obtained from knowing and pursue life saving treatment. 

Ripoll-Vera et al. investigated the molecular autopsy results of 123 consecutive decedents who died from sudden cardiac death at age 50 or younger. They state that genetic analysis was performed in 62 cases, which makes me question why the remaining 61 did not undergo genetic analysis. They describe their overall yield as 67.7% by lumping together all identified variants, including variants of uncertain significance. This number is exceptionally high compared to other cohort studies and may be confusing to some casual readers, as variants of uncertain significance cannot be used to determine diagnosis, and many are reclassified as benign overtime. 

Their true yield is 30%, meaning 30% of decedents had an identifiable pathogenic or likely pathogenic variant. These are variants that have enough evidence supporting their disease causing nature. Even this yield is high compared to results from a cohort study I worked on in 2019 evaluating the yield of molecular autopsy in New York City. The differences in yield could be for a number of reasons, including more stringent variant interpretation, and a larger and more diverse cohort in New York City. 

Sudden cardiac death can affect anyone. The impact of molecular autopsy goes beyond a single individual or family. This work has greater public health implications which is evidenced by research into the utility of molecular autopsy happening across the globe. One cannot exalt the value of our technical capabilities without recognizing the importance of genetic counseling accompanying the process, as families attempt to navigate a fraught new frame of reference after the loss of a loved one due to a sudden cardiac death. Genetic counselors are able to be a sounding board and translator to families seeking answers, and help empower people to act on their own risks by pursuing evaluation, testing, and treatment.

Do any of the following apply to you or your family? 

• A personal or family history of cardiovascular conditions that affect the heart muscle (cardiomyopathy) and that can have a hereditary basis (Ex. Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy)
• A personal or family history of cardiovascular conditions that affect the electrical system of the heart (arrhythmia) and that can have a hereditary basis (ex. Long QT Syndrome, Brugada syndrome)
• A family history of unexplained sudden death or cardiac arrest
• A personal or family history of very high cholesterol (ex. LDL >190 mg/dl)

A genetic counselor can assess your risk using your personal and family history to consider a testing strategy and provide follow up care to review the implications of the results.

References & Further Reading

Ripoll-Vera Tomás et al. “Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing.” September 8, 2020. Rev Esp Cardiol (Engl Ed)

Williams N, Maderski E, Stewart S, et al. “Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services.” August 22, 2019. Journal of Genetic Counseling.

Nori Williams, MS, CGC is a certified genetic counselor and holds licenses in IA, IL, IN, SD, VA, NJ, PA, OH, and KY. For over three years, Nori worked at the Office of the Chief Medical Examiner, assisting with interpretation of genetic variants and supporting families impacted by cardiomyopathies and arrhythmias. She is now the cardiac lead at PWNHealth. She is the current President Elect of the New York State Genetics Task Force. 

View Nori’s full profile and schedule an appointment with her here.