Key result
A novel heterozygous loss-of-function mutation in the CACNA1C gene (p.Lys800Thr) caused a prominent reduction in Cav1.2 channel current amplitude, resulting in a new Cav1.2 channelopathy.
Why the study?
Complex neuropsychiatric-cardiac syndromes can be genetically determined, but syndromic presentations linking short QT syndrome to specific genetic mutations remain to be characterized.
Case Report (n=1)
Identifies a novel pathogenic loss-of-function mutation in CACNA1C causing a new Cav1.2 channelopathy characterized by short QT syndrome and severe neuropsychiatric and dental manifestations.
Hypothesis-generating for syndromal short QT with neuropsychiatric features; leaves open validation in larger cohorts.
Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.
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Endres et al. (2020) conducted a case report in Cav1.2 channelopathy / Short QT syndrome (n=1). CACNA1C loss-of-function mutation (p.Lys800Thr) was evaluated on Cav1.2 channel function. A novel heterozygous loss-of-function mutation in the CACNA1C gene (p.Lys800Thr) caused a prominent reduction in Cav1.2 channel current amplitude, resulting in a new Cav1.2 channelopathy.
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