A Chinese infant with CACNA1C p.C1021R variant expands clinical phenotype of CACNA1C-related disorder

Abstract

CACNA1C-related disorder (CRD), a severe multisystem disorder caused by variants of CACNA1C gene, presents significant diagnostic and management challenges due to its rarity and variable expressivity. This study leverages a detailed longitudinal case report and comprehensive literature review to expand the phenotypic spectrum of CRD with Timothy syndrome (TS) features associated with the CACNA1C NM_001129830.1: c.3061 T > C (p.Cys1021Arg) variant. We describe an individual with CRD exhibiting a severe multisystem phenotype including classic features like syndactyly, profound neurological symptoms, and cardiac arrhythmias. Critically, our detailed clinical and genetic analysis identified previously undocumented features for this specific variant: cerebral infarction, as well as a combined T-cell and B-cell immunodeficiency characterized by specific lymphocyte dysregulation. These novel findings necessitate refined diagnostic protocols and tailored management strategies. By redefining CRD with TS features as a profoundly multisystem disorder, this expanded understanding facilitates improved prognostication, genetic counseling, and targeted therapeutic interventions, aiming to transform management from unpredictable complications into predictable, preventable components, ultimately enhancing quality of life and survival.