Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

Abstract

We report familial cardiac conduction disease (FCCD) in a 3-generation pedigree, including some family members with congenital junctional ectopic tachycardia (JET) (Fig. 1A). The proband presented during a febrile illness at 3.5-years of age with variable atrio-ventricular (AV) block (1st, 2nd, and 3rd degrees) together with left anterior fascicular block (LAFB) and right bundle branch block (RBBB) (Fig. 1B). Viral studies and echocardiogram were normal and he received a pacemaker; he subsequently developed clinical junctional tachycardia. Family history revealed a maternal grandmother with RBBB diagnosed at 5 years of age. The electrocardiogram (ECG) from the proband's mother revealed sinus rhythm (SR), 1st degree AV block and a nonspecific intraventricular conduction delay. Clinical genetic testing of SCN5A did not reveal any disease-associated mutations. Subsequently she gave birth to identical twin girls. Both girls had rapid JET in the immediate post-natal period that was initially difficult to control. There was rate dependent RBBB and LAFB in both children prior to use of antiarrhythmic drugs. The arrhythmia has resolved in one twin but persists in the other as a catecholamine dependent accelerated junctional rhythm/congenital JET that is modified by propranolol therapy (Fig. 1C). The resting ECGs now both show LAFB and intermittent incomplete RBBB. The mother has subsequently developed symptomatic palpitations and shows electrocardiographic features consistent with typical atrioventricular nodal re-entrant tachycardia (AVNRT) on symptom-rhythm correlation observed on loop recorder. Thus, the conduction defects in this family were of varying severity and the relationship to congenital JET in the three children is important as it is well recognized that congenital JET may progress to heart block [ 1 Henneveld H. Hutter P. Bink-Boelkens M. et al. Junctional ectopic tachycardia evolving into complete heart block. Heart. 1998; 80: 627-628 Crossref PubMed Scopus (23) Google Scholar , 2 Villain E. Vetter V.L. Garcia J.M. et al. Evolving concepts in the management of congenital junctional ectopic tachycardia. A multicenter study. Circulation. 1990; 81: 1544-1549 Crossref PubMed Scopus (211) Google Scholar ]. At this stage the conduction abnormalities are minor in the twins who presented with the JET and have not progressed.