Inherited HeartDiseases

Research Areas

• Genetics of Dilated Cardiomyopathy (DCM)
• Genetics of Atrial Fibrillation
• Zebrafish heart disease models

Research Overview

Research work undertaken in the Sr Bernice Research Program in Inherited Heart Diseases focusses on two of the most common types of heart problems: dilated cardiomyopathy (DCM) and atrial fibrillation. Inherited gene variants are being increasingly recognised as important causes of heart disease, but very little is known about what these genetic factors are and how they affect heart function. Led by Professor Diane Fatkin, her team of researchers is trying to find the faulty genes that cause inherited forms of dilated cardiomyopathy (DCM) and atrial fibrillation. They are also trying to discover how these gene changes affect the heart’s contraction and rhythm. The researchers are using cutting-edge technology, including next-generation sequencing techniques, to find genetic variants in families with these disorders. To understand the molecular defects underpinning disease, the team is using a number of cell-based and animal models, including zebrafish. The overall objective is to define the genetic causes of dilated cardiomyopathy (DCM) and atrial fibrillation and to translate this understanding to new approaches to diagnosis, treatment and prevention.

There are 3 key projects underway in the Inherited Diseases Laboratory, led by Professor Diane Fatkin;

1. Genetics of dilated cardiomyopathy and atrial fibrillation

The aim of this project is to identify disease-causing rare variants in families in which these disorders appear as a heritable trait. The team is exploring whole-genome sequencing and novel bioinformatics tools to discover gene mutations.

2. Zebrafish models of adult-onset heart disease

The team is developing new zebrafish models using genetic engineering technologies such as TALENs and CRISPR/cas9 as well as new techniques to study heart function. The group is one of the first in the world to use high frequency echocardiography to study heart size and contraction in adult zebrafish. The team is also adapting other techniques that are commonly used to assess human heart function, including electrocardiography (ECG) and stress testing.

3. Genes and environment

A combination of clinical studies in families and intervention studies in zebrafish models is being used to look at interactions between genetic susceptibility and environmental factors.

1. Fatkin D, Calkins H, Elliott P, James CA, Peters S, Kovacic JC. Contemporary and future approaches to precision medicine in inherited cardiomyopathies. JACC Focus Seminar 3/5. J Am Coll Cardiol 2021;77:2551-2572.
2. Giudicessi JR*, Ackerman MJ*, Fatkin D*, Kovacic JC. Precision medicine approaches to cardiac arrhythmias. JACC Focus Seminar 4/5. J Am Coll Cardiol 2021;77:2573-2591. (*Co-first authors)
3. Taliun D,Fatkin D. Abecasis GR. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 2021;590:290-299.
4. Akhtar MM, Lorenzini M, Cicerchia M, Ochoa JP, Hey TM, Molina MS, Restrepo-Cordoba MA, Dal Ferro M, Stolfo D, Johnson R, Larranaga-Moreira JM, Robles-Mezcua A, Rodriguez-Palomares JF, Casas G, Pena-Pena ML, Lopes LR, Gallego-Delgado M, Franaszczyk M, Laucey G, Rangel-Sousa D, Basurte M, Palomino-Doza J, Villacorta E, Bilinska Z, Friere JL, Pinilla JM, Barriales-Villa R, Fatkin D, Sinagra G, Garcia-Pavia P, Gimeno JR, Mogensen J, Monserrat L. Elliott PM. European Cardiomyopathies Initiative Investigators. Phenotype and prognosis of dilated cardiomyopathy caused by truncating variants in the titin (TTN) gene. Circ Heart Fail 2020;13:e006832.
5. Wong GR, Nalliah CJ, Lee G, Voskoboinik A, Prabhu S, Parameswaran R, Sugumar H, Anderson RD, Ling LH, McLellan A, Johnson R, Sanders P, Kistler PM, Fatkin D*, Kalman JM*. Genetic susceptibility to atrial fibrillation is associated with atrial electrical remodelling and adverse post-ablation outcome. JACC: Clin Electrophysiol 2020;6:1509-1521. (*Co-senior authors)
6. Fatkin D, Huttner IG, Kovacic JC, Seidman JG, Seidman CE. Precision medicine in the management of dilated cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;74:2921-2938.
7. Horvat C, Johnson R, Lam L, Munro J, Mazzarotto F, Roberts AM, Herman DS, Parfenov M, Haghighi A, McDonough B, DePalma SR, Keogh AM, Macdonald PS, Hayward CS, Roberts A, Barton PJ, Felkin LE, Giannoulatou E, Cook SA, Seidman JG, Seidman CE, Fatkin D. A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy. Genet Med 2019;21:133-143.
8. Minoche AE, Horvat C, Johnson R, Gayevskiy V, Morton SU, Drew AP, Woo K, Statham AL, Lundie B, Bagnall RD, Ingles J, Semsarian C, Seidman JG, Seidman CE, Dinger ME, Cowley MJ, Fatkin D. Genome sequencing as a first-line genetic test in dilated cardiomyopathy. Genet Med 2019;21:650-662.
9. Huttner IG, Wang LW, Santiago CF, Horvat C, Johnson R, Cheng D, von Frieling-Salewsky M, Hillcoat K, Bemand TJ, Trivedi G, Braet F, Hesselson D, Alford K, Hayward CS, Seidman JG, Seidman CE, Feneley MP, Linke WA, Fatkin D. A-band titin truncation in zebrafish causes dilated cardiomyopathy and hemodynamic stress intolerance. Circ Genom Precis Med 2018;11:e002135.
10. Roselli C, Chaffin MD, Weng LC, Fatkin D, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 2018;50:1225-1233.
11. Fatkin D, Santiago CF, Huttner IG, Lubitz SA, Ellinor PT. Genetics of atrial fibrillation: state of the art in 2017. Heart Lung Circ 2017;26:894-901.
12. Fatkin D, Johnson R, McGaughran J, Weintraub RG, Atherton JJ, CSANZ Genetics Writing group. Position statement on the diagnosis and management of familial dilated cardiomyopathy. Heart Lung Circ 2017;26:1127-1132.
13. Fatkin D, Huttner IG. Titin truncating mutations in dilated cardiomyopathy: the long and short of it. Curr Opin Cardiol 2017;32:232-238.
14. Wang LW, Huttner IG, Santiago CF, Kesteven SH, Yu ZY, Feneley MP, Fatkin D. Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models. Dis Model Mech 2017;10:63-76.