Cardiomyopathy, Dilated, 1e

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1E can be caused by mutation in the cardiac sodium channel gene SCN5A (600163).

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Clinical Features

Greenlee et al. (1986) reported a large family of German and Swiss ancestry with dilated cardiomyopathy, conduction defect, and arrhythmia. The phenotype included sinus node dysfunction in adolescence, supraventricular tachyarrhythmia, and progressive atrial ventricular and intraventricular conduction delay that led to permanent pacing in most cases. The phenotype was also characterized by a progression toward atrial dilation, frequently followed by right ventricular dilation and, in some cases, led to ventricular dilation and dysfunction.

Cheng et al. (2010) described 2 families with dilated cardiomyopathy (CMD) and arrhythmias. Pedigree A was a non-Hispanic white family, previously studied by Hershberger et al. (2008) (family C.3), with early-onset CMD occurring at approximately 29 years of age and prominent conduction system disease. The proband and his 2 affected sibs required implantable cardiac defibrillators (ICDs) at ages 32, 31, and 23 years, respectively. The proband's son had asymptomatic premature ventricular complexes (PVCs) detected during screening at 10 years of age and was diagnosed with CMD at age 17. Pedigree B was an African American family with CMD, also previously studied by Hershberger et al. (2008) (family C.7), in which the asymptomatic proband was diagnosed with CMD at 31 years of age after a screening echocardiogram showed left ventricular enlargement and low-normal ejection fraction. At 37 years of age, he developed symptoms of heart failure, with a 15-mm increase in left ventricular end-diastolic size and an ejection fraction that had decreased to 10%. An ICD was placed 1 year later, and he died suddenly at 42 years of age. His mother, who had a history of conduction system disease, was diagnosed with CMD at age 53 and died 5 years later of 'sudden cardiac death and arrhythmia,' according to her death certificate. His 72-year-old maternal aunt had cardiac arrhythmias including atrial fibrillation, first-degree atrioventricular block, and premature atrial contractions (PACs); she had an ejection fraction of 65% with left ventricular enlargement and tachyarrhythmias, but was not diagnosed with CMD.

Laurent et al. (2012) studied 21 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and CMD. Age at diagnosis ranged from 24 weeks of gestation to 62 years (mean age, 20 years). Symptoms included palpitations, dyspnea, and syncope. Patients exhibited paroxysmal atrial arrhythmia, atrial flutter, and atrial fibrillation, as well as PVC rates ranging from 3,500 to 86,000 per 24-hour period. Six patients were diagnosed with CMD, and 4 patients required placement of ICDs. Sudden death was reported in 5 individuals. The electrocardiographic phenotype was remarkably consistent, with narrow sinus and junctional QRS complexes competing with various complexes showing an RBBB or LBBB pattern, corresponding to PVCs with superior or inferior axes. There was no QT prolongation or ST segment elevation. Electrophysiologic studies demonstrated that the PVCs originated from the Purkinje tissue.

Mann et al. (2012) studied a large kindred with CMD and multiple arrhythmias, including PVCs of variable morphologies. A striking feature of the EKG tracings from affected family members was the relative paucity of normally conducted sinus beats, with the majority of beats being PVCs, including narrow PVCs of probably high septal origin that had varying morphology and axis, as well as wide PVCs of left and right bundle branch type. PACs and accelerated junctional rhythms were also seen. Of the 16 affected individuals, 6 had documented atrial fibrillation, and 3 received pacemakers for symptomatic bradycardia or complete heart block in later life. Electrophysiologic studies done in 4 individuals uniformly showed multiple PVC foci in the left and right ventricles, with no inducible ventricular arrhythmias. Five patients had prophylactic placement of ICDs. Eight individuals had a diagnosis of CMD, including 2 asymptomatic young men who were diagnosed only as a result of family screening; in all other cases, the diagnosis was preceded by a history of palpitations. CMD was present in 7 of 9 affected males but in only 1 of 7 affected females. There was 1 clinically unaffected mutation carrier in this family (see MOLECULAR GENETICS), a 56-year-old man with a normal EKG and echocardiogram. Mann et al. (2012) noted that affected family members who had shown little or no benefit from standard heart failure therapy who, after genetic diagnosis, were switched to drugs with sodium channel-blocking properties, exhibited dramatic reductions in numbers of PVCs, with recovery of normal left ventricular function over approximately 6 months.

Mapping

Olson and Keating (1996) studied the family reported by Greenlee et al. (1986) with dilated cardiomyopathy associated with sinus node dysfunction, supraventricular tachyarrhythmias, conduction delay, and stroke. Linkage to D3S2303 was identified with a 2-point lod score of 6.09 at a recombination fraction of 0.00. Haplotype analyses mapped this locus to a 30-cM region of 3p25-p22, excluding candidate genes encoding a G protein, GNAI2 (139360), a calcium channel, CACNL1A2 (114206), a sodium channel, SCN5A (600163), and an inositol-triphosphate receptor, ITPR1 (147265).

Molecular Genetics

In affected members of the family with dilated cardiomyopathy reported by Greenlee et al. (1986), McNair et al. (2004) identified heterozygosity for an asp1275-to-asn mutation (D1275N; 600163.0034) in the SCN5A gene.

Groenewegen et al. (2003) had found the same D1275N mutation, coinherited with polymorphisms in the atrial-specific junction channel protein connexin-40 (GJA5; 121013), in a family with atrial standstill (ATRST1; 108770). None of the affected members in this family had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question the relationship of the SCN5A mutation to dilated cardiomyopathy in the family reported by McNair et al. (2004). McNair et al. (2005) responded that the younger age of the affected members studied by Groenewegen et al. (2003) as well as additional genetic or environmental factors may account for the difference between the 2 families.

Olson et al. (2005) analyzed the SCN5A gene in 156 unrelated patients with dilated cardiomyopathy who were negative for mutations in several known CMD genes and identified 5 different heterozygous mutations in 4 probands from multigenerational families segregating CMD and cardiac arrhythmias and in 1 patient with a de novo mutation (see, e.g., 600163.0027, 600163.0038-600163.0039). All of the mutations altered highly conserved residues in the transmembrane domains of SCN5A, and each was found to segregate with disease in the respective family. Among individuals with an SCN5A mutation, 27% had early features of CMD, 38% had CMD, and 43% had atrial fibrillation.

In affected members of 2 unrelated families with CMD and conduction system disease, Hershberger et al. (2008) identified heterozygosity for 2 different missense mutations in the SCN5A gene, R222Q (600163.0046) and I1835T (600163.0047), respectively.

In 3 unrelated families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene, which was fully penetrant and strictly segregated with the cardiac phenotype in each family. The mutation was not found in 600 control chromosomes, and haplotype analysis showed that a founder effect for these 3 families was very unlikely. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Because only 6 of the 19 patients carrying the R222Q mutation had CMD, and the cardiomyopathy recovered at least partially with antiarrhythmia treatment and a reduction in the number of premature ventricular contractions, Laurent et al. (2012) suggested that CMD might be a consequence of the arrhythmia and not directly linked to the mutation.

In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. All 6 patients had cardiac arrhythmias and 5 had left ventricular dysfunction, which was mild in 1 individual; the proband's brother, who carried the mutation, had only an ectopic atrial rhythm with normal left ventricular systolic function. Catheterization and mapping revealed that there was no consistent evidence of bundle branch reentry or fascicular potentials preceding ectopic beats, and there was no single site suitable for ablation. The results were consistent with the triggered activity originating from variable regions of the septum, most likely the left fascicle or possibly Purkinje muscle junctions and transitional cells. The bigeminy was suppressed by intravenous administration of the sodium channel blocker lidocaine. Patch-clamp studies demonstrated differential leftward voltage-dependent shifts in activation and inactivation of mutant channels, consistent with increasing channel excitability at precisely the voltages corresponding to the resting membrane potential of cardiomyocytes. Nair et al. (2012) stated that their results supported the notion that patients harboring the R222Q mutation develop cardiomyopathy as a result of the arrhythmia.

In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including PVCs of variable morphologies, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram, but was not found in 200 control chromosomes.