Abstract
Although relatively rare, inherited primitive cardiac disorders (IPCDs) in athletes have a deep social impact since they often present as sudden cardiac death (SCD) of young and otherwise healthy persons. The diagnosis of these conditions is likely underestimated due to the lack of shared clinical criteria and to the existence of several borderline clinical pictures. We will focus on the clinical and molecular diagnosis of the most common IPCDs, namely hypertrophic cardiomyopathies, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy, and left ventricular non-compaction. Collectively, these conditions account for the majority of SCD episodes and/or cardiologic clinical problems in athletes. In addition to the clinical and instrumental tools for the diagnosis of IPCD, the viral technological advances in genetic testing have facilitated the molecular confirmation of these conditions. However, genetic testing presents several issues: the limited sensitivity (globally, around 50%), the low prognostic predictive value, the probability to find pathogenic variants in different genes in the same patient, and the risk of non-interpretable results. In this review, we will analyze the pros and cons of the different clinical approaches for the presymptomatic identification, the diagnosis and management of IPCD athletes, and we will discuss the indications to the genetic testing for patients and their relatives, particularly focusing on the most complex scenarios, such as presymptomatic tests, uncertain results, and unexpected findings.
Highlights
Inherited primitive cardiac disorders (IPCDs) comprise a wide and heterogeneous group of conditions
It has become clear that allelic variants in the same gene can be associated with different phenotypes, increasing the difficulties inherent to the interpretation of genetic test results. These findings suggest that the variable phenotypic spectrum of IPCDs cannot be only accounted for by classical Mendelian mechanisms, and point toward the involvement of an oligogenic model with strong environmental influences
(0.44–0.47 s) and 25–35% of individuals with a pathogenic variant in one of the long QT syndrome (LQTS) genes has a normal QT interval [25, 26]. This latter observation deserves some additional comments: at this stage, it is very difficult to establish whether the finding of a variant considered disease causing in asymptomatic patients is due to reduced penetrance or if, in the light of more recent concepts of molecular genetics, it is the consequence of a wrong interpretation, and the observed DNA change in a variants of uncertain significance (VUS), or even a rare benign, not clinically relevant, variation
Summary
Inherited primitive cardiac disorders (IPCDs) comprise a wide and heterogeneous group of conditions. The diagnosis of LQTS is apparently easy, but 15% of subjects in the general population have a QT interval >0.44 s (0.44–0.47 s) and 25–35% of individuals with a pathogenic variant in one of the LQTS genes has a normal QT interval [25, 26] This latter observation deserves some additional comments: at this stage, it is very difficult to establish whether the finding of a variant considered disease causing in asymptomatic patients is due to reduced penetrance or if, in the light of more recent concepts of molecular genetics, it is the consequence of a wrong interpretation, and the observed DNA change in a VUS, or even a rare benign, not clinically relevant, variation.
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