CACNA1C – Short QT Syndrome

Short QT syndrome (SQTS) is an autosomal dominant arrhythmia characterized by abbreviated ventricular repolarization, predisposing to syncope, atrial arrhythmias, and sudden cardiac death. The L-type calcium channel α1-subunit Cav1.2, encoded by CACNA1C, is critical for the plateau phase of the cardiac action potential. Loss-of-function variants in CACNA1C reduce inward calcium current (I_Ca,L), thereby shortening the QT interval and manifesting as SQTS (MonDO:0000453).

In a single-patient report, a 34-year-old German male with a heterozygous missense mutation c.2399A>C (p.Lys800Thr) exhibited a markedly shortened QT interval alongside neuropsychiatric features. Electrophysiological studies in HEK-293 cells demonstrated a prominent reduction in calcium current amplitude without gating changes, indicating a trafficking defect leading to loss of function (PMID:33203140).

A Chinese family with hypertrophic cardiomyopathy, early repolarization, atrioventricular block, and SQTS harbored a trigenic set of mutations. CACNA1C c.5918G>C (p.Arg1973Pro) co-segregated with early repolarization and short QT in the proband and his daughter (n=2 affected relatives) and produced a 68.4% reduction of I_Ca in TSA201 cells (PMID:28427417).

In a Japanese cohort of 312 unrelated probands referred for inherited arrhythmias, six distinct CACNA1C variants were identified in seven individuals with SQTS, including c.2573G>A (p.Arg858His). Although half of these carriers were asymptomatic, three experienced syncope or ventricular fibrillation, underscoring variable penetrance (PMID:23575362).

Collectively, these studies describe nine unrelated probands with heterozygous CACNA1C variants in SQTS and demonstrate consistent loss-of-function effects on Cav1.2 currents, with segregation in one family. The weight of genetic and functional evidence supports a Moderate clinical validity classification for the CACNA1C–SQTS association.

Key Take-home: CACNA1C should be included in genetic testing panels for individuals with unexplained short QT intervals, as heterozygous loss-of-function variants confer a clinically actionable arrhythmia risk.

References

• International journal of molecular sciences • 2020 • New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel CACNA1C Loss-Of-Function Mutation. PMID:33203140
• Journal of translational medicine • 2017 • Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome. PMID:28427417
• Circulation Journal • 2013 • L-type calcium channel mutations in Japanese patients with inherited arrhythmias. PMID:23575362

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