P2A054: A Retrospective Descriptive Study of Patients Evaluated in a Tertiary Genetic Heart Rhythm Clinic with Pathogenic Variants in the cacna1c-encoded Voltage-dependent L-type Calcium Channel (CaV1.2)

Background: The CACNA1C (Calcium voltage-gated channel subunit alpha1 C) gene encodes for the alpha1 L-type voltage-gated calcium channel (CaV1.2), which mediates calcium influx into excitable cells, such as cardiac myocytes and neurons. Pathogenic variants in CACNA1C underlie a spectrum of conditions that involves the cardiac, neurologic, and psychologic system. In this study, we reported the spectrum of clinical findings, genotypes, treatment, and outcomes of patients with CACNA1C variants who were evaluated for sudden cardiac death-predisposing genetic heart diseases (GHDs).

Methods: We conducted a retrospective review of patients evaluated and treated at Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic between July 2000 and November 2022 to identify those with a pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) in CACNA1C. Electronic medical records were reviewed for patient demographics, clinical characteristics, and genotypes.

Results: A total of 4,774 patients were evaluated for GHD, of which 47 patients (1%) had a P/LP or VUS genetic variant(s) in CACNA1C (57.4% female; mean age at diagnosis 23.3 years old; mean QTc 481 msec. Overall, 20 were diagnosed with long QT syndrome (LQTS; 42.6%), 7 with Timothy syndrome (TS; 14.9%), 2 with cardiac only Timothy syndrome (COTS, 4.3%), 1 with Brugada syndrome (BrS, 2.1%) and 17 with a VUS. Among the 17 patients with a VUS in CACNA1C, 7 didn’t have any disease phenotype, 8 had only cardiac manifestations including mitral valve prolapse, ventricular arrhythmias, and cardiomyopathy. Interestingly, 2 VUS-positive subjects (T941I and E1115K) also had extracardiac manifestations. One patient had only extracardiac findings including developmental delay, seizures, abnormal dentition, and autism. The other patient had both cardiac and extracardiac findings including QT prolongation, autism, and developmental delay. In general, a total of 9 patients (including all 7 TS patients) had extracardiac manifestations, including 6 patients with syndactyly (12.8%), 4 with autism (8.5%), 3 with hypoglycemia (6.4%), and 3 with neurodevelopmental delay (6.4%). Overall, 23 (48.9%) patients received non-selective beta-blocker, and 19 (40.0%) patients received an implantable cardioverter-defibrillator (ICD). Notably, 4 out of 7 patient (57.1%) with non-penetrant LQTS were not treated prophylactically, 9 out of 17 VUS-positive individuals (52.9%) didn’t receive any medical treatment or devices. Five (10.6%) patients had at least 1 GHD-associated breakthrough cardiac event during follow-up (including 3 patients with TS).

Conclusion: Patients with CACNA1C mutations in our clinic showed a wide range of diagnoses and disease severity, with the majority of patients showing a phenotype of QT prolongation with or without extracardiac features (LQTS or TS). Treatment options for arrhythmia in CACNA1C patient with or without a known pathogenic mutation may include multiple medication therapy, ICDs, or sympathetic denervation. Preventative measures only therapy is a reasonable option for some patients with CACNA1C-positive but phenotype-negative substrates.