Expanding the phenotype of CACNA1C mutation disorders
Lindsey Gakenheimer-Smith1, Lindsay Meyers2, Derek Lundahl1
1Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA.
Molecular Genetics & Genomic Medicine
|April 2, 2021
Summary
Pathogenic CACNA1C variants cause Timothy syndrome. A specific variant, p.R518C, previously linked to cardiac-only disease, is now shown to present with a broader range of cardiac conditions in a new family study.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Pathogenic variants in CACNA1C, encoding the L-type Ca2+ channel, cause Timothy syndrome, a multi-system disorder.
- A specific CACNA1C variant (p.R518C) was previously associated with a cardiac-only form of Timothy syndrome, including congenital heart disease, hypertrophic cardiomyopathy (HCM), and long QT syndrome (LQTS).
Observation:
- This study investigated a four-generation family with the p.R518C CACNA1C variant.
- The family exhibited a wider spectrum of clinical manifestations than previously reported for this specific variant.
Findings:
- Family members displayed cardinal features of CACNA1C disorders, including LQTS, congenital heart disease, HCM, and sudden cardiac death.
- Additionally, affected individuals manifested atrial fibrillation and sick sinus syndrome, expanding the known cardiac phenotype.
Implications:
- This expands the recognized cardiac phenotype associated with CACNA1C variants.
- The findings highlight the significant variable expressivity of L-type Ca2+ channel mutations, impacting clinical presentation and diagnosis.
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