New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel Loss-Of-Function Mutation.

Dominique Endres, Niels Decher, Isabell Röhr, Kirsty Vowinkel, Katharina Domschke, Katalin Komlosi, Andreas Tzschach, Birgitta Gläser, Miriam A Schiele, Kimon Runge, Patrick Süß, Florian Schuchardt, Kathrin Nickel, Birgit Stallmeyer, Susanne Rinné, Eric Schulze-Bahr, Ludger Tebartz van Elst

Journal: International journal of molecular sciences 2021;21(22):8611

PMID: 33203140

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Abstract

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.

Address: Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.; Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany.; Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.; Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.; Department of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.; Department of Neurology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany.

DOI: 10.3390/ijms21228611

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MeSH Terms: Adult, Arrhythmias, Cardiac, Autistic Disorder, Calcium Channels, L-Type, Channelopathies, Dental Enamel, Humans, Loss of Function Mutation, Male, Mood Disorders