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Review
. 2016 Dec 27;68(25):2871-2886.
doi: 10.1016/j.jacc.2016.08.079.

Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy

Michael A Burke  1 , Stuart A Cook  2 , Jonathan G Seidman  3 , Christine E Seidman  4
Affiliations
Review

Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy

Michael A Burke et al. J Am Coll Cardiol. .

Abstract

Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients.

Keywords: dilated cardiomyopathy; genetic testing; genetics; hypertrophic cardiomyopathy; molecular etiology; restrictive cardiomyopathy.

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Figures

FIGURE 1
FIGURE 1. A Schematic of Definitive (Bolded) and Posited HCM Genes With the Subcellular Localization of the Encoded Proteins
All pathogenic genes encode sarcomere proteins. Putative HCM genes encode these and sarcomere-associated molecules. HCM = hypertrophic cardiomyopathy.
FIGURE 2
FIGURE 2. A Schematic of Definitive and Posited DCM Genes With the subcellular Localization of the Encoded Proteins
Pathogenic genes encode proteins that participate in many diverse biological processes of cardiomyocytes. DCM = dilated cardiomyopathy.
FIGURE 3
FIGURE 3. Titin Mutations in DCM
(A) Schematic representation and electron micrograph demonstrating the location of titin protein in the sarcomere. Titin molecules are composed of 4 protein domains, including the Z-disc (Z), I-band, A-band, and M-band, that span half the length of the sarcomere. (B) Bar graph demonstrating the percentage of identified TTN truncating variants in cohorts with a range of cardiovascular physiology. (C) Schematic demonstrating the location of TTN truncating variants with respect to protein domain. The percent spliced-in is a measure of exon usage in TTN messenger RNA from different cardiac tissue samples and demonstrates reduced exon usage in the I-band, which would exclude the expression of most mutations located in this domain. In contrast, mutations causing DCM reside in fully expressed exons. Adapted from Roberts et al. (88). DCM = dilated cardiomyopathy; OR = odds ratio.
FIGURE 3
FIGURE 3. Titin Mutations in DCM
(A) Schematic representation and electron micrograph demonstrating the location of titin protein in the sarcomere. Titin molecules are composed of 4 protein domains, including the Z-disc (Z), I-band, A-band, and M-band, that span half the length of the sarcomere. (B) Bar graph demonstrating the percentage of identified TTN truncating variants in cohorts with a range of cardiovascular physiology. (C) Schematic demonstrating the location of TTN truncating variants with respect to protein domain. The percent spliced-in is a measure of exon usage in TTN messenger RNA from different cardiac tissue samples and demonstrates reduced exon usage in the I-band, which would exclude the expression of most mutations located in this domain. In contrast, mutations causing DCM reside in fully expressed exons. Adapted from Roberts et al. (88). DCM = dilated cardiomyopathy; OR = odds ratio.
FIGURE 3
FIGURE 3. Titin Mutations in DCM
(A) Schematic representation and electron micrograph demonstrating the location of titin protein in the sarcomere. Titin molecules are composed of 4 protein domains, including the Z-disc (Z), I-band, A-band, and M-band, that span half the length of the sarcomere. (B) Bar graph demonstrating the percentage of identified TTN truncating variants in cohorts with a range of cardiovascular physiology. (C) Schematic demonstrating the location of TTN truncating variants with respect to protein domain. The percent spliced-in is a measure of exon usage in TTN messenger RNA from different cardiac tissue samples and demonstrates reduced exon usage in the I-band, which would exclude the expression of most mutations located in this domain. In contrast, mutations causing DCM reside in fully expressed exons. Adapted from Roberts et al. (88). DCM = dilated cardiomyopathy; OR = odds ratio.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Genetics of Inherited Cardiomyopathies
Clinical (A) or cascade genetic (B) screening strategies for familial cardiomyopathies. Initial clinical and genetic screening, as well as interval follow-up, is recommended as per guidelines (10,143,144).
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