Half of patients with pathogenic CACNA1C variants, excluding classical Timothy syndrome, were referred for suspected cardiomyopathies, highlighting overlooked QT prolongation.
Pathogenic CACNA1C variants are frequently associated with cardiomyopathies in adults, emphasizing the importance of recognizing these variants beyond classical long QT syndrome.
Absolute Event Rate: 0% vs 0%
Abstract Background Structural heart diseases and cardiac channelopathies are often considered distinct, yet CACNA1C variants have been implicated in both. Timothy syndrome (TS), a rare disorder caused by CACNA1C variants, was initially described in pediatric patients with multisystem involvement, primarily due to missense variants affecting Gly402 and Gly406. Subsequent studies identified additional missense variants, some with predominantly cardiac phenotypes, often in adults. While long QT syndrome (LQTS) and life-threatening arrhythmias are key features, hypertrophic cardiomyopathy (HCM) has also been reported, though not universally. Objective To assess the referral phenotypes of patients carrying pathogenic or likely pathogenic (P/LP) CACNA1C variants in a large cohort undergoing genetic testing for suspected inherited cardiovascular diseases. Methods We performed next-generation sequencing (NGS) on probands using a customized gene library, which is updated every two years. The CACNA1C gene has been included since January 2013. Identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical phenotypes and demographic data were obtained from the genetic testing request forms. Results We analyzed the CACNA1C gene using NGS in 42,658 unrelated probands. A total of six P/LP missense variants (p.Gly402Ser-exon8A, p.Gly406Arg, p.Arg518Cys, p.Arg518His, p.Arg858His, p.Arg860Gln) were identified in 18 probands (50% female). The most frequently affected residue in our cohort was Arg518 (n=10). Probands carrying variants at residues Gly402 and Gly406 (n=3) were pediatric patients referred for LQTS and exhibited an early-onset and/or severe phenotype, consistent with previous reports. Among probands carrying other variants, ages ranged from 12 to 81 (mean=40). The most prevalent phenotype was LQTS (n=6), followed by isolated HCM (n=5). One proband was referred for dilated cardiomyopathy (DCM), two for LQTS with cardiomyopathy, and one for sudden cardiac death (SCD). For further details, see Table 1. Conclusion In our cohort, half of the patients with P/LP CACNA1C variants, excluding classical TS cases, were referred due to suspected cardiomyopathies. Our findings emphasize the importance of recognizing CACNA1C variants in adult patients with cardiomyopathies, as associated QT prolongation may be overlooked. Identifying these variants as disease-causing is crucial for risk assessment and appropriate clinical management, as standard risk calculators may be inadequate for these patients.
Brogger et al. (Sat,) reported a other. Half of patients with pathogenic CACNA1C variants, excluding classical Timothy syndrome, were referred for suspected cardiomyopathies, highlighting overlooked QT prolongation.