Sudden cardiac death (SCD) of athletes is a
topical issue. “Borderline cardiac abnormalities”, which occur in
~2% of elite male athletes, may result in SCD, which may have
a genetic base. Genetic analysis may help identify pathological
cardiac abnormalities. We performed phenotype-guided
genetic analysis in athletes who, pre-participation, showed
ECG and/or echo “borderline” abnormalities, to discriminate
subjects at a greater risk of SCD.
Methods: We studied 24 elite athletes referred by the National
Federation of Olympic sports; and 25 subjects seeking eligibility
to practice agonistic sport referred by the Osservatorio
Epidemiologico della Medicina dello Sport della Regione
Campania. Inclusion criteria: a) ECG repolarization borderline
abnormalities; b) benign ventricular arrhythmias; c) left
ventricular wall thickness in the grey zone of physiology versus
pathology (max wall thickness 12-15 mm in females; 13-16 mm
in males). Based on the suspected phenotype, we screened
subjects for the LMNA gene, for 8 sarcomeric genes, 5
desmosomal genes, and cardiac calcium, sodium and
potassium channel disease genes.
Results: Genetic analysis was completed in 37/49 athletes, 22
competitive and 27 non-competitive athletes, showing
“borderline” clinical markers suggestive of hypertrophic
cardiomyopathy (HCM,n. 24), dilated cardiomyopathy (n. 4),
arrhythmogenic right ventricular dysplasia/cathecholaminergic
polymorphic ventricular tachycardia (ARVD/CPVT, n. 11), long
QT syndrome (LQTS, n. 4), sick sinus syndrome (SSS, n. 5),
Brugada syndrome (BrS, n. 1). We identifyed 11 mutations in
9 athletes (an ARVD athlete was compound heterozygote for
the PKP2 gene and an HCM athlete was double heterozygote
for the MYBPC3 and TNNT2 genes): 3 known mutations
related to LQTS, HCM and ARVD, respectively, and 8 novel
mutations, located in the SCN5A, RyR2, PKP2, MYBPC3 and
ACTC1 genes. The new mutations were absent in ~800 normal
chromosomes and were predicted “probably damaging” by in
silico analysis. Patch clamp analysis in channelopathies
indicated for some mutation abnormal biophysical behavior of
the corresponding mutant protein.
Conclusion: Genetic analysis may help distinguish between
physiology and pathology in athletes with clinically suspected
heart disease