Genetics and genetic testing of dilated cardiomyopathy: a new perspective

Abstract

The completion of the Human Genome Project was a landmark achievement, but as clinical genetic testing becomes more mainstream, the extent of remarkable genetic variation is increasingly being appreciated. Newer DNA sequencing technology can now complete the sequencing of an entire human genome several times over in a matter of days, but this will undoubtedly add new challenges to the difficulty of distinguishing true pathogenic variants from benign variants in diagnostic genetics and in the research setting. The recent discovery of the role of titin gene (TTN) mutations in dilated cardiomyopathy (DCM) will make genetic testing in this disease more efficient. Furthermore, better understanding of genotype-phenotype associations will assist clinicians in identifying early stages of disease and providing more appropriate treatments. This high level of complexity requires an expert genetic team to offer counseling and to manage, deliver, and follow-up over time the results of genetic testing, which is particularly important for screening of family members potentially at risk. In DCM, genetic testing may be useful for the identification of non-carriers and asymptomatic carriers, as well as for prevention strategies, sport recommendations, and defibrillator implantation. It can also guide reproductive decision-making including utilization of pre-implantation genetic diagnostic strategies.

Figure 1

Titin mutations in DCM. Top: the cardiac sarcomere including titin (orange), the thick filaments (green rods with globular heads) and thin filaments (green coiled ovals), Z-disk (red), I-band (blue), A-band (green), and M-band (purple). Middle: DCM TTN splicing and copy-number mutations (blue), nonsense and frameshift mutations (red); truncating mutations in controls and subjects with hypertrophic cardiomyopathy (black), truncating mutations in congenital myopathy (light purple) or limb-girdle muscular dystrophy (dark purple). Bottom: TTN isoforms and sequence variants. From Herman et al., with permission (Herman et al., 2012).

Figure 2

Survival in patients with LMNA mutations. Kaplan-Meier event-free survival from the date of first visit stratified by 4 independent risk factors (RF): non-sustained ventricular tachycardia, left ventricular ejection fraction <45% at the first visit to the cardiologist, being male, and truncation mutations. The event was defined as occurrence of malignant ventricular arrhythmias (appropriate implantable cardioverter-defibrillator treatment, cardiopulmonary resuscitation, or sudden cardiac death). From van Rijsingen et al., with permission (van Rijsingen et al., 2012).

Figure 3

Survival in patients with sporadic DCM and familial DCM. Analysis of survival free from heart-transplant (HTx) in sporadic (solid line) and non-proband familial DCM (dotted line). D/HTx, death/heart transplant. From Moretti et al., with permission (Moretti et al., 2010).