PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL

Arnold Palmer Hospital for Children Orlando Health FL

Centre for Clinical Genetics Sydney Children's Hospitals Network and University of New South Wales Sydney Australia

Charles University Motol University Hospital Prague Czech Republic

Department of Biochemistry and Genetics Angers University Hospital Angers France

Department of Human Genetics Inselspital Bern University Hospital University of Bern Switzerland

Department of Neurology Rosamund Stone Zander Translational Neuroscience Center Boston Children's Hospital Harvard Medical School Boston MA

Department of Pediatrics University of Louisville Norton Children's Hospital Louisville KY

Department of Radiology Armand Trousseau Hospital APHP Sorbonne University Paris France

Division of Genetic Medicine Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Division of Genetics and Genomic Medicine Department of Pediatrics Washington University School of Medicine St Louis MO

IGF Université de Montpellier CNRS INSERM Montpellier France; LabEx Ion Channel Science and Therapeutics Montpellier France

Leeds Teaching Hospitals NHS Trust Leeds United Kingdom

Pediatric Neurogenetics Laboratory Department of Genetics Armand Trousseau Hospital AP HP Sorbonne Université Paris France; Reference Center for Cerebellar Malformations and Congenital Diseases Armand Trousseau Hospital APHP Sorbonne Université Paris France; Université Paris Cité INSERM UMR1163 Imagine Institute Developmental Brain Disorders Laboratory Paris France

Pediatric Neurology Institute Dana Dwek Children's Hospital Tel Aviv Medical Center and Faculty of Medical and Health Science Tel Aviv University Tel Aviv Israel

Reference Center for Cerebellar Malformations and Congenital Diseases Armand Trousseau Hospital APHP Sorbonne Université Paris France

Service de Médecine Génomique des Maladies Rares Necker Enfants Malades University Hospital APHP Paris France

Tel Aviv Sourasky Medical Center Genetic Institute Tel Aviv Israel

Unité fonctionnelle de Génétique Médicale Centre Hospitalier Universitaire Tours France

Université Paris Cité INSERM UMR1163 Imagine Institute Developmental Brain Disorders Laboratory Paris France

Université Rouen Normandie INSERM U1245 CHU de Rouen Department of Genetics and Reference Center for Developmental Disorders Rouen France

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