Expanding the phenotype of CACNA1C mutation disorders

Abstract

Background: Pathogenic variants in the L-type Ca²⁺ channel gene CACNA1C cause a multi-system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac-only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra-cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations.

Methods: A four-generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great-uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant.

Results: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome.

Conclusion: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L-type Ca²⁺ channel.

Keywords: CACNA1C; atrial fibrillation; cardiac-only Timothy syndrome; sick sinus syndrome.

FIGURE 1

Single‐family pedigree of patients harboring the CACNA1C p.R518C pathogenic variant and their associated diagnoses (key below figure). The red circle indicates the index patient