A number sign (#) is used with this entry because of evidence that cardiac conduction disease with or without dilated cardiomyopathy (CCDD) is caused by heterozygous mutation in the TNNI3K gene (613932) on chromosome 1p31.

Theis et al. (2014) reported a Caucasian family of German ancestry in which 7 members spanning 3 generations exhibited cardiac conduction disease and atrial tachyarrhythmias; some also developed dilated cardiomyopathy (CMD). The proband presented with supraventricular tachycardia at 20 years of age, with a normal echocardiogram and unexplained left anterior fascicular block. Family history was remarkable for arrhythmia in several relatives, chronic CMD and congestive heart failure in the proband's mother and maternal grandmother, and sudden unexplained childhood death in a maternal aunt. When the patient was 31 years old, Holter monitoring documented paroxysmal multifocal atrial tachycardia and frequent premature ventricular contractions, with unremarkable echocardiogram. At age 39, he developed dyspnea and had left ventricular enlargement with a reduced ejection fraction (45%). Endomyocardial biopsy showed nonspecific but typical histopathologic features of CMD, including mild focal myocyte hypertrophy and interstitial fibrosis. Ultrastructural analysis of a right ventricular endomyocardial biopsy from the proband showed variable loss of myofilaments and mitochondriosis, with some mitochondria exhibiting architectural disorganization of cristae with vacuolization and degenerative changes. Some nuclei were distinctly abnormal and showed numerous amorphic intranuclear inclusions, and similar inclusions were observed in the sarcoplasm, associated with areas of marked myofilament loss; in addition, many severely swollen mitochondria were observed. After the proband underwent 18 months of medical treatment to effect reverse ventricular remodeling, his CMD resolved on echocardiogram. At 50 years of age, he was asymptomatic with an ejection fraction of 55%, but his conduction disease had progressed to bifascicular block. He had 5 living relatives with infra-hisian conduction disease with variable expression of atrial tachyarrhythmias, including atrial fibrillation (AF)/flutter and ectopic/multifocal atrial tachycardia. In 3 affected children in this pedigree, the arrhythmia was successfully suppressed with combination medical therapy and catheter-based ablation of right atrial foci.

Xi et al. (2015) reported a family in which 5 members over 3 generations had cardiac conduction disease with or without congenital junctional ectopic tachycardia. The proband was a boy who presented at 3.5 years of age during a febrile illness with a variable atrioventricular (AV) block (first, second, and third degrees) together with left anterior fascicular block and right bundle branch block (RBBB). He received a pacemaker. He subsequently developed clinical junctional tachycardia. His maternal grandmother had RBBB diagnosed at age 5 years. His mother had first-degree AV block and a nonspecific intraventricular conduction delay. She subsequently developed symptomatic palpitations and electrocardiographic features consistent with typical AV nodal re-entrant tachycardia. Twin sisters of the proband had rapid junctional ectopic tachycardia in the immediate postnatal period. Both also had left anterior fascicular block and intermittent incomplete RBBB.

Fan et al. (2018) reported a 3-generation Chinese family with conduction system disease and dilated cardiomyopathy. The 26-year-old male proband came to attention because of a syncopal episode during exercise; an earlier syncopal episode had occurred 3 years earlier. The electrocardiogram (ECG) showed a sinus bradycardia and cardiac dilatation. Echocardiography confirmed left ventricular and left atrial enlargement, and he was given a diagnosis of dilated cardiomyopathy. The proband's grandfather died during sleep of unknown causes at age 42 years. His father had left ventricular and atrial dilatation and a cardiac conduction defect. His paternal uncle had a history of syncope at age 30 and had left atrial and ventricular dilatation, but no abnormalities on ECG. His paternal aunt had a prior syncopal episode, but refused testing.

Podliesna et al. (2019) described 23 affected individuals from 3 unrelated large multigenerational families with supraventricular tachycardias (SVTs), conduction disease, and cardiomyopathy, who all had the same missense mutation in the TNNI3K gene (see MOLECULAR GENETICS). Symptoms ranged from palpitations to syncope to cardiac arrest, usually in association with physical exertion. Life-threatening events such as ventricular tachyarrhythmia or history of 'heart attack,' and/or cardiac arrest occurred in 4 patients, including 1 patient (3-III.1) who died after cardiac arrest during soccer practice at age 13. Other family members were also reported to have experienced sudden unexplained death. Most affected individuals exhibited SVTs, including atrial tachycardia that was usually multifocal, junctional tachycardia, atrial fibrillation, and atrioventricular nodal reentrant tachycardia. Ventricular tachycardia (VT) was seen in 2 individuals, 1 of whom (3-III.7) required cardioversion for sustained VT; the mechanism of VT in this patient was thought to be a bundle branch reentry on electrophysiologic (EP) study. History of CMD or echocardiographic evidence of left ventricular dysfunction was present in 5 of 20 individuals for whom data were available, and 2 patients had suspicion of mild right ventricular dilation and/or wall thinning. Baseline ECG, available in 14 patients, showed evidence of conduction defects in the majority of individuals, including 9 with left axial deviation, 3 with borderline or prolonged PR interval (200 to 220 ms), and 2 with borderline or prolonged QRS duration (118 to 120 ms). Prolonged HV interval (60-78 ms) was seen in 5 (83%) of 6 patients for whom data were available, with one showing fractionated-split His electrogram on an EP study. In addition, 7 of the 14 affected individuals with ECG data also demonstrated either borderline or significant prolongation of the QTc interval (459 to 526 ms).

The transmission pattern of CCDD in the family reported by Theis et al. (2014) was consistent with autosomal dominant inheritance.

Theis et al. (2014) performed genomewide genotyping and linkage analysis in a family with cardiac conduction disease with or without dilated cardiomyopathy. The authors mapped 2 equally plausible disease gene loci on chromosomes 13q12 and 1p36.1-p31, with peak lod scores of 2.4 for both loci. Construction of haplotypes revealed linkage to a 10-Mb region at 13q12 and a 57-Mb region at 1p36.1-p31.

In a Caucasian family of German ancestry with cardiac conduction disease with or without dilated cardiomyopathy, Theis et al. (2014) performed whole-exome sequencing and identified a heterozygous missense mutation in the TNNI3K gene (G526D; 613932.0001) on chromosome 1p31. The mutation segregated with disease in the family and was not found in more than 7,600 exomes/genomes in publicly available databases. Screening of the TNNI3K gene in 125 unrelated probands with familial CMD or AF as well as in 40 individuals with sporadic CMD or cardiac conduction disease revealed no pathogenic variants.

Using whole-exome sequencing in a 3-generation pedigree with cardiac conduction system disease, Xi et al. (2015) identified a heterozygous missense mutation in the TNNI3K gene (T539A; 613932.0002). The mutation was confirmed by Sanger sequencing and segregated with the disease in the family. Xi et al. (2015) noted that the T539 residue has been shown to be key to controlling kinase activity and accessibility of the ligand-binding pocket to selective kinase inhibitors.

Using whole-exome sequencing in a 3-generation Chinese family with cardiac conduction disease and dilated cardiomyopathy, Fan et al. (2018) identified a heterozygous splice site mutation in the TNNI3K gene (613932.0003). The mutation was confirmed by Sanger sequencing and segregated with the disorder in the family. The mutation was not found in the 1000 Genomes Project or dbSNP (build 132) databases or in 200 healthy local controls. Real-time qPCR analysis showed reduced TNNI3K mRNA expression of about 61% compared with controls, consistent with nonsense mediated decay.

In all 23 affected individuals from 3 unrelated large multigenerational families with CCDD, Podliesna et al. (2019) identified heterozygosity for the same missense mutation in the TNNI3K gene (E768K; 613932.0004). No clinical information was available for 3 additional family members who tested positive for the E768K variant or for 1 obligate carrier.