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

• Published in: International journal of molecular sciences 2020-11, Vol.21 (22), p.8611
• Main Authors: Endres, Dominique, Decher, Niels, Röhr, Isabell, Vowinkel, Kirsty, Domschke, Katharina, Komlosi, Katalin, Tzschach, Andreas, Gläser, Birgitta, Schiele, Miriam A, Runge, Kimon, Süß, Patrick, Schuchardt, Florian, Nickel, Kathrin, Stallmeyer, Birgit, Rinné, Susanne, Schulze-Bahr, Eric, Tebartz van Elst, Ludger
• Format: Article
• Language: English
• Subjects: Adult; Age; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Autistic Disorder - pathology; CACNA1C; Calcium; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Case Report; CaV1.2; Channel gating; Channelopathies - genetics; Channelopathies - metabolism; Channelopathies - pathology; Channelopathy; Communication; Computer science; Dental enamel; Dental Enamel - abnormalities; Dental Enamel - metabolism; Dental Enamel - pathology; dental enamel defect; Electrocardiography; Humans; Loss of Function Mutation; Lysine; Male; Mood Disorders - genetics; Mood Disorders - metabolism; Mood Disorders - pathology; Mutation; Pathogenicity; Psychotropic drugs; short QT syndrome; Teeth
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228611

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 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.