ClinVar Genomic variation as it relates to human health

In 6 affected members over 3 generations of a non-Hispanic white family with cardiomyopathy and conduction system disease (CMD1E; 601154), Hershberger et al. (2008) identified heterozygosity for a 36683G-A (numbering per SeattleSNP) transition in exon 6 of the SCN5A gene, resulting in an arg222-to-gln (R222Q) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls. In 19 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the 665G-A (R222Q) mutation in the SCN5A gene, located in the voltage-sensing S4 segment of domain I. The mutation, which was fully penetrant and strictly segregated with the cardiac phenotype in each family, was not found in 600 control chromosomes; 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. Heterologous expression studies in Chinese hamster ovary K1 cells revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. The activation and inactivation of cells expressing equimolar combinations of wildtype and R222Q channels showed properties intermediate between those seen in cells expressing either wildtype or mutant channels alone. The changes in mutant channel properties were predicted to produce hyperexcitability of R222Q sodium channels. In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphology, 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. Patch-clamp studies showed that the R222Q mutation did not alter sodium channel current density, but did shift steady-state parameters of activation and inactivation to the left. Using a voltage ramp protocol, normalized current responses of mutant channels were of earlier onset and greater magnitude than wildtype. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant; this was supported by the clinical observation that PVC frequency increased during periods of low heart rate at rest and at night, and was reduced by high heart rates during exercise. Patients responded to sodium-channel blocking drugs with early and substantial reductions in PVCs followed by normalization of CMD over time. (less)