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Eur Heart J. 2018 Nov 21;39(44):3925-3931. doi: 10.1093/eurheartj/ehy502.

Modifier genes for sudden cardiac death.

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Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo, 22, Milan, Italy.
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, Monza, Italy.
Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Piazzale Brescia 20, Milan, Italy.
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Searle 8-510, East Superior Street, Chicago, IL, USA.


Genetic conditions, even those associated with identical gene mutations, can present with variable clinical manifestations. One widely accepted explanation for this phenomenon is the existence of genetic factors capable of modifying the consequences of disease-causing mutations (modifier genes). Here, we address the concepts and principles by which genetic factors may be involved in modifying risk for cardiac arrhythmia, then discuss the current knowledge and interpretation of their contribution to clinical heterogeneity. We illustrate these concepts in the context of two important clinical conditions associated with risk for sudden cardiac death including a monogenic disorder (congenital long QT syndrome) in which the impact of modifier genes has been established, and a complex trait (life-threatening arrhythmias in acute myocardial infarction) for which the search for genetic modifiers of arrhythmic risk is more challenging. Advances in understanding the contribution of modifier genes to a higher or lower propensity towards sudden death should improve patient-specific risk stratification and be a major step towards precision medicine.

[Available on 2019-11-21]

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