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2 Inferolateral T-wave inversion in athletes: a phenotype-genotype correlation

Introduction Significant T-wave inversion in young asymptomatic athletes is rare, but poses a significant clinical challenge. Pre-participation sports screening programs often identify such subjects. The clinical suspicion that such ECG changes represent an occult cardiomyopathy leads to diagnostic and therapeutic dilemma. It has been suggested that such ECG changes may be due to mutations in genes encoding myofilament proteins and forme fruste hypertrophic cardiomyopathy. We sought to genotype a prospective cohort of such subjects with no discernible phenotype identified in our unit over a 3 year period. Methods Ten athletes were referred from external pre-participation screening. All exhibited prominent deep symmetrical T wave inversion in the inferolateral leads (figure 1). All had negative family history for sudden death and had a normal phenotype based on 2D transthoracic echocardiography, Holter monitoring, stress testing and cardiac MRI. Next generation DNA sequencing was used to screen a panel of 133 cardiac-specific genes associated with cardiomyopathy and/or channelopathy. Results were confirmed by standard Sanger sequencing.Abstract 2 Figure 1 T wave inversion in the inferolateral leads Results All subjects were male with a mean age of 39 years (age range 18–54 years). 7 had no evidence of sequence variation in the genetic panel. 3 patients demonstrated variants of uncertain significance in 5 different cardiac genes (table 1): alpha-2-actinin (ACTN2), myopalladin (MYPN), the calcium channel genes CACNA1C and TRPM4 and potassium channel gene KCNQ1. Both ACTN2 and MYPN genes code for structural proteins in the sarcomeric complex and other variants in these proteins have been described in hypertrophic and dilated cardiomyopathy cases. The 3 other variants found in ion channel genes have not been described in cardiomyopathies. At 3 year follow up, one patient had undergone detraining and his ECG interestingly showed complete resolution of all T wave changes. He did not have any demonstrated variants.Abstract 2 Table 1 Variants of uncertain significance Patient age Mutation(s) identified DNA Protein Consequence Classification 29 ACTN2 c.1058G>A p.(Arg353Gln) Missense VUS* MYPN c.2829T>G p.(Ile943Met) Missense VUS 54 KCNQ1 c.1246G>A p.Val416Met Missense VUS 48 CACNA1C c.2340G>A c.2340G>A(p.=) Splice region, synonymous VUS TRPM4 c.2953+5G>C - Splice region, intron VUS *Variant of uncertain significance Conclusions The substantial absence of mutations in cardiac myofilament genes and the heterogeneous sequence variations identified in this study suggest that inferolateral repolarization abnormalities in athletes without a phenotype do not represent HCM or a cardiomyopathy. Moreover, the absence of a family history and the benign clinical course of the subjects in this study also suggest that this is a benign athletic repolarization syndrome. This was the first study to assess a phenotype-genotype correlation in this population. Further genetic studies need to be undertaken in this area.