Key result
CACNA1C II-III loop variants were associated with similar arrhythmic event rates as other variants (53% vs 48%, P=0.41) but a higher history of sudden death (60% vs 0%, P=0.03).
Why the study?
Pathogenic gain-of-function variants in CACNA1C cause LQT8, prompting a study to describe electrocardiographic features and utilize molecular modelling for mechanistic insights.
Do variants in the II-III loop region of CACNA1C affect the clinical and electrocardiographic phenotype in patients with LQT8 compared to other pathogenic variants?
Observational (n=23)
Yes
Do variants in the II-III loop region of CACNA1C affect the clinical and electrocardiographic phenotype in patients with LQT8 compared to other pathogenic variants?
Absolute Event Rate: 53% vs 48%
p-value: p=0.41
The majority of pathogenic variants in CACNA1C-mediated LQT8 cluster in the II-III loop, which is associated with a higher risk of sudden death despite shorter QTc intervals compared to other variants.
II-III loop CACNA1C variants may signal higher sudden death risk despite shorter QTc in LQT8; leaves open prospective validation for genotype-specific stratification.
AIMS: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. METHODS AND RESULTS: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. CONCLUSION: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.
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Mellor et al. (2019) conducted an observational in Type-8 long QT syndrome (LQT8) (n=23). CACNA1C II-III loop variants vs. Other CACNA1C pathogenic/likely pathogenic variants was evaluated on Arrhythmic events (p=0.41). CACNA1C II-III loop variants were associated with similar arrhythmic event rates as other variants (53% vs 48%, P=0.41) but a higher history of sudden death (60% vs 0%, P=0.03).
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