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AF Symposium 2020

For A-Fib Patients Under Age 40: Genetic Testing Before Your Catheter Ablation?

by Steve S. Ryan

Patrick Ellinor, MD

Patrick Ellinor, MD

Background: We have previously reported on the extraordinary work of Dr. Patrick Ellinor of Massachusetts General Hospital and his colleagues world-wide in examining the genetics and genome sequencing of A-Fib, and the genetic susceptibility to A-Fib. This group has been doing genetic testing of A-Fib for over 25 years at over 60 sites throughout the world. (See AF Symposium 2017 World-Wide Studies on Genetic A-Fib)
Gene vs Genome: A gene is a part of a DNA molecule; The genome is the total DNA in a cell.

Over the years, researchers have identified 100 distinct genetic loci for A-Fib. (A locus is a specific, fixed position on a chromosome where a particular gene or genetic marker is located.)

Finding the Genome for A-Fib

In a presentation entitled “AF Under Age 40―Genetic Testing Before Ablation?”, Dr. Ellinor of Massachusetts General Hospital described what is perhaps the culmination of years of work―the discovery that the muscle protein titin-gene (TTN mutation) is the main gene linked to genetic A-Fib.

This is major news! All these efforts by Dr. Ellinor and his many colleagues throughout the world have finally paid off.

Loss-of-function mutation: A mutation that results in reduced or abolished protein function.

The Titin gene is critical for normal heart function. It’s the largest gene in the human genome. About one out of 250 people carries a Loss-Of-Function (LOF) mutation in one of their TTN genes.

In a recent study which examined genome-wide associations in 1,546 people with A-Fib and 41,593 controls, 14% of people who have this mutation have A-Fib. No other gene locus even comes close (see blue arrow in chart below). These TTN mutations have been associated with early-onset A-Fib.

Caption: High-confidence loss-of-function (LOF) variants in TTN among atrial fibrillation (AF) cases and controls cases in UK Biobank. Source: Choi, S. H.

Patients with TTN Mutation Much More Likely to Develop A-Fib

Dr. Ellinor described “finger printing” of a few hundred thousand genetic variants scattered throughout the genome. These capture about 90% of the differences between any one of us.

Having the TTN mutation gives you a six-fold increased chance of developing A-Fib.

His studies compare associated regions and look for spikes such as the TTN mutation. People with the TTN mutation have a six-fold increase in the likelihood of developing A-Fib.

There is also a much smaller TTN association with heart failure and cardiomyopathy. They have done cardiac MRIs on many patients with the TTN mutation.

What Do We Do with This TTN Data?

Dr. Hugh Calkins from Johns Hopkins asked the question on everyone’s mind.

“Now that we have this TTN data, what do we do with it?”

Dr. Ellinor described very preliminary research where they divide patients into low, medium and high risk, then document how the patients do after their catheter ablation.

One might speculate that catheter ablation results with high risk patients wouldn’t be as successful. But right now, this is speculation.

Patients Need to Know If They Have the TTN Gene Mutation

So, will doctors tell their patient if they are at high risk of developing A-Fib? Most patients would want to know.

Popular genetic testing companies include Ancestry and 23andMe.

Dr. Ellinor advises his patients that genetic testing companies offer testing for the TTN mutation as part of an “arrhythmia test” panel for around $100.

Perhaps, patients already diagnosed with early-onset A-Fib would benefit from knowing if they have the TTN mutation.

For patients with the TTN mutation: Your doctor could perform a cardiac MRI and more closely examine and monitor your results. In addition, your children could be tested for the TTN mutation.

The Bottom Line for Patients: Dr. Ellinor recommends genetic testing early and offered to anyone 40 years old or younger with A-Fib.

Added 5/18/21:

Dr. David Darbar of the Un. of Illinois, Chicago states that the Titin gene. associated with an increased risk of atrial fibrillation, poses a significantly increased risk for heart failure in Black and Hispanic/Latinx people.

Editor’s Comments:

Finding the TTN gene/genome responsible for so much A-Fib is a hugely important discovery!
And equally important is finding out that so many people have the TTN LOF mutation. The TTN mutation may cause or make it more likely that someone will develop A-Fib. This is invaluable information both for patients and for the doctors treating them.
But how this TTN information can or will be used in treating patients is a whole new, barely explored world.
A great deal of work lies ahead to better understand the precise mechanisms by which genomic variation causes Atrial Fibrillation.

Participate in A-Fib Genetic Studies

If you and at least 3 other members of your family have A-Fib, you can become involved in this potentially very important research. Contact the studies at Mass. General Hospital or Vanderbilt University.

Patrick T. Ellinor, MD, PhD, Director, Cardiac Arrhythmia Service
Marisa Shea, RN,  Research Nurse
Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114
617-724-7780, Email: mshea1(at)

Vanderbilt University also welcomes families with A-Fib for their genetic studies. Contact the Vanderbilt Atrial Fibrillation Registry (they also have an AF Ablation Registry)

Diane Crawford, RN
Vanderbilt University Medical Center, 1266 MRB IV, Nashville, TN 37232-0575
(615) 322-0067, Email: Diane.n.crawford(at)

References for this article
Choi, S. H. et al. Monogenic and Polygenic Contributions to Atrial Fibrillation Risk, Results From a National Biobank. Circulation Research. 2020 Jan 17;126[2]: 200-9.

Choi, S. H. et al. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. Jama Network, December 11, 2018.

Parmet, Sharon. New mutation raises risk for AFib, heart failure for people of color. UCI Today, May 5, 2021.

Darbar. F. et al. Association of Rare Genetic Vriants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals. JAMA Cardiol. May 5, 2021. doi:10.1001/jamacardio.2021.0994.



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