hereditary long qt syndrome ( lqts ) is a genetic disorder resulting in delayed ventricular repolarization manifesting as a prolonged qt interval on the electrocardiogram and an increased propensity for polymorphic ventricular tachycardia ( torsade de pointes ) , syncope , and sudden arrhythmic death in young adults without structural abnormalities . originally described as romano  ward and jervell and langenielsen syndromes , breakthroughs in genetic and molecular analyses have allowed for more specific descriptions of a similar disease phenotype 1 . point mutations on five genes primarily affecting the function of the cardiac potassium current : kcnq1 ( lqts1 ) , kcnh2 ( lqts2 ) , scn5a ( lqts3 ) , mink ( lqts5 ) , and mirp1 ( lqts6 ) have been implicated . mutations in the kcnq1 gene have been reported in 3962% of patients with autosomaldominant lqts where sudden cardiac death is often triggered by physical activity 2 . the clinical triad of atrial fibrillation , cardiomyopathy , and sudden cardiac death in association with lqts has not been previously described . we report a case of cardiac arrest with vigorous exercise , paroxysmal atrial fibrillation , and development of cardiomyopathy where subsequent genetic analysis identified a novel mutation in the kcnq1 gene and lqts1 . a 30yearold african american male developed ventricular fibrillation and sudden cardiac death with strenuous boot camp exercises while training with the united states marine corps at the age of 23 years . he was successfully resuscitated in the field and emergently transported to a nearby hospital for further medical care . ischemic workup and evaluation for secondary causes of sudden cardiac arrest in addition to echocardiography were reassuring . serial electrocardiography led to a diagnosis of lqts and the patient received an implantable cardioverter defibrillator . four years after this episode the patient established care with our facility with evaluation diagnosing paroxysmal atrial fibrillation . despite adequate rate control and routine medical care , the patient subsequently developed left ventricular systolic dysfunction in the following 2 years . the patient 's medications included aspirin 81 mg daily , carvedilol 12.5 mg twice daily , simvastatin 20 mg daily , and lisinopril 10 mg daily . figure 1 displays his resting electrocardiogram showing a qt interval of 480 msec and rate corrected qt ( qtc ) interval of 522 msec . transthoracic echocardiography showed moderate reduction in left ventricular systolic function with an estimated left ventricular ejection fraction of 40% in a global distribution . the left ventricular ( lv ) dysfunction was a new finding compared to prior echocardiograms and workup for ischemic or secondary causes of new onset lv dysfunction were unremarkable . based on his history of sudden cardiac death , family history , and implications for his siblings and children , genetic testing ( which includes complete coding region and splice junctions of the following 12 genes currently known to be associated with lqts : kcnq1 , kcnh2 , scn5a , ank2 , kcne1 , kcne2 , kcnj2 , cacna1c , cav3 , scn4b , akap9 , and snta1 ) revealed a point mutation resulting in a change of codon configuration from amino acids sequence gag ( glutamic acid ) to ggg ( glycine ) at the e146 g position in the kcnq1 gene using gene sequencing analysis . over continued followup , the patient suffered from multiple episodes of exerciseinduced ventricular tachycardia terminated by defibrillator therapies . to the best of our knowledge , this is the first report of the novel , likely pathogenic e146 g mutation that manifests as phenotypic lqts1 resulting in sudden cardiac death , atrial fibrillation , and cardiomyopathy . the e146 g mutation on the kcnq1 gene results in an amino acid substitution that is predicted to alter secondary protein structure . 3 studied the e146k mutation , which lies in the same residue , and linked its association with lqts1 . further support of the functional importance of this region of the gene is suggested by missense mutations ( such as t144a , q147r , and a150 g ) in nearby residues that have been reported in the human gene mutation database in association with lqts and atrial fibrillation 4 . the e146 g mutation was not observed in approximately 6500 individuals of european or african american heritage as part of the national heart lung blood institute ( nhlbi ) exome sequencing project indicating it is not likely to represent a benign polymorphism 5 . analogous to reports in families with lqts3 syndrome , we hypothesize this mutation may be associated with left ventricular dysfunction based on the patient 's course and family history 6 . syncope is a common presenting complaint , and it can be difficult to decide when to expand the evaluation beyond a thorough history and physical examination . lqts1 may present with a mildly prolonged qt interval at baseline , however the qt interval fails to shorten with increased chronotropy associated with exertion . this leads to an increase in the qtc interval with chronotropy and greater propensity of ventricular arrhythmia . other arrhythmic syndromes such as preexcited atrial fibrillation ( atrial fibrillation with an accessory pathway / wolff  parkinson  white syndrome ) and catecholaminergic polymorphic ventricular tachycardia in addition to structural diseases such as hypertrophic cardiomyopathy , arrhythmogenic right ventricular cardiomyopathy , anomalous origin of coronary arteries , occult coronary artery disease , and myocarditis ( or prior myocarditis with subsequent ventricular scarring ) can present with exertional syncope or cardiac arrest with exertion . the patient presented herein had a significantly prolonged qtc interval , twave inversions , and lateral q waves on his ecg ( fig . the abnormal ecg did not demonstrate pathognomonic findings , and additional testing was required to assess for other structural abnormalities . although the risk of sudden cardiac death with vigorous exercise is a rare yet often publicized event , cardiac events are triggered by exercise in most patients with lqts1 7 . societies such as the american heart association have advised patients with lqts against participation in  high intensity athletic or training activities 8 which contradict exercise recommendations for patients with chronic heart failure 9 . our patient experienced one episode of exerciseinduced sudden cardiac death as detailed above and multiple icd therapies at later dates triggered by vigorous activity . balancing the above recommendations for our patient with lqts1 and cardiomyopathy , we suggested modest , monitored exercise . in our case , the patient carried a clinical diagnosis of a disease with an autosomaldominant inheritance pattern . he had a daughter and several siblings placing importance on the identification of disease causing mutations for counseling of his family members . genetic testing , however , is not yet considered standard assessment for patients presenting with exertional syncope 10 . with regard to exercise recommendations , genotype  phenotype correlations lack granularity to assist in prediction of individual risk associated with exercise for patients with lqts . genetic testing of the most common genes involved in the lqts has value in certain clinical scenarios . as in the case reported , identification of a point mutation in the proband facilitates screening of family members , may influence treatment decisions , and identify those with  carrier moreover , as mutation detection is vital to the development and role of genetic screening , novel findings add to the catalog of known mutations to help guide ongoing work analyzing the genotype  phenotype link . in conclusion , the case we present highlights the importance of recognizing exerciseassociated symptoms in patients with lqts and differentiating this condition from others with predisposition for ventricular arrhythmias . through genetic testing we found a novel , pathogenic mutation on the kcnq1 gene leading to lqts1 with possible genetic predisposition for development of atrial fibrillation and left ventricular systolic dysfunction . this adds to the growing understanding of the genetic basis behind lqts and emerging discoveries between genotypic  phenotypic links in this syndrome . targeted genetic testing in patients with high pretest probability of this disorder may influence management of patients and their family members . for our patient , we provided genetic counseling to discuss the implications of this finding for himself and his family , including targeted testing of the e146 g variant in the kcnq1 gene for his siblings and daughter . clinicians should be alarmed when evaluating patients with exertional syncope and expedite workup with electrocardiograms , echocardiogram , longterm cardiac telemetry monitoring , and referral to specialists if the diagnosis remains unclear .
key clinical messageexerciseinduced syncope should alert clinicians to the possibility of lqts and must be distinguished from other malignant causes of syncope such as hypertrophic cardiomyopathy , catecholaminergic ventricular tachycardia , and arrhythmogenic right ventricular cardiomyopathy . 
 emerging genotype  phenotype links have connected mutations resulting in lqts with risk of developing atrial fibrillation and cardiomyopathy .