A cross-sectional study of the neuropsychiatric phenotype of CACNA1C-related disorder


      • CACNA1C-related disorder (CRD) is a rare genetic disorder with a high risk of neurodevelopmental disorders and risk of cardiac arrhythmia.
      • Among 24 individuals with CRD we found high rates of developmental delay, neurologic, and psychiatric symptoms, including a 37.5% prevalence of epilepsy.
      • Whether or not an individual had cardiac symptoms did not change these risks.
      • These findings suggest that individuals with CRD should be screened and receive care for these common symptoms.



      CACNA1C encodes the voltage gated L-type calcium channel CaV1.2. A specific gain of function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relate to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development.


      Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher’s exact test for comparison of categorical variables between participants with and without cardiac arrhythmia.


      Twenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention deficit hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia.


      In our CRD cohort there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.

      List of abbreviations:

      ADHD (attention deficit hyperactivity disorder), ASD (autism spectrum disorder), CRD (CACNA1C-related disorder), LQTS (long QT interval syndrome), LTCC (L-type calcium channel), OCD (obsessive compulsive disorder), TS (Timothy syndrome), TS1 (Timothy syndrome type 1), TS2 (Timothy syndrome type 2)


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