Key result
High-pathogenicity CACNA1C variants in transmembrane and cytoplasmic domains are linked to significantly higher mortality.
Why the study?
Several cardiac conditions are potentially associated with pathogenic CACNA1C variants, but genotype-phenotype correlations and risk stratification related to survival remain unclear.
Do specific CACNA1C variants and their domains correlate with clinical phenotypes and survival in affected patients?
Observational (n=102)
Do specific CACNA1C variants and their domains correlate with clinical phenotypes and survival in affected patients?
p-value: p=<0.001
CACNA1C variants with high ACMG scores and those located in cytoplasmic or transmembrane domains are associated with higher mortality, enabling better risk stratification.
CACNA1C variant-phenotype links require cautious clinical interpretation; leaves open precise risk stratification pending larger prospective cohorts.
Background CACNA1C is a gene encoding the CaV1.2 calcium channel and several cardiac conditions are potentially associated with pathogenic variants in this gene. The aim of this study is to explore genotype-phenotype correlations related to CACNA1C ever described variants and vast phenotypic spectrum.MethodsWe analyzed 102 patients with CACNA1C variants (CACNA1Cv) (9 our cohort and 93 from literature). We studied the association between CACNA1Cv and clinical parameters: arrhythmias, structural heart defects, cardiomyopathy and survival. We followed the American College Medical Genetics (ACMG) scoring system to grade variants’ pathogenicity and their domains.Results CACNA1Cvwith high ACMG scores were associated with higher mortality than variants with lower scores (p < 0.001). CACNA1Cv in Cytoplasmic and Transmembrane domains were associated with higher mortality than other domains (p = 0.005). Multivariate analysis for higher ACMG scores, indicates cardiomyopathy and a lesser extent domain, as independent risk factor for mortality (p = 0.031 and p = 0.04). Cytoplasmic domain variants were frequently associated with long-QT syndrome; C-terminal variants were often linked to Brugada syndrome. Parental mosaicism was relatively high (4–5%) and must not be overlooked in parents’ phenotypic analysis and in calculation of disease recurrence riskConclusionTo the best of our knowledge, this is the first study trying to create genotype-phenotype correlation and better risk stratification in CACNA1Cv in relation to survival and long-term results.
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Baban et al. (2020) conducted an observational in CACNA1C variants (n=102). CACNA1C variants with high ACMG pathogenicity scores vs. CACNA1C variants with lower ACMG pathogenicity scores was evaluated on Mortality (p=<0.001). CACNA1C variants with high ACMG pathogenicity scores and those located in the Cytoplasmic and Transmembrane domains were associated with significantly higher mortality.
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