Date of Award

Spring 2023

Document Type

Open Access Thesis


Genetic Counseling

First Advisor

Laina Lusk


Pathogenic variants in the CACNA1A gene disrupt a calcium channel expressed in the central nervous system, causing a variety of neurological and psychiatric features collectively known as CACNA1A-related disorders. Gain-offunction and loss-of-function of this channel are both well-established mechanisms of disease, but specific genotype-phenotype correlations have remained unclear. Previous research has been limited by small sample sizes, with some studies noting significant intrafamilial variation and reduced penetrance. This study aimed to collect and analyze genotypic and phenotypic data from a large sample of individuals with CACNA1A-related disorders published in the literature and in two patient cohorts. Using the Human Phenotype Ontology, we harmonized phenotypic data and systematically analyzed features within and between subgroups. We described 416 individuals diagnosed with CACNA1A-related disorders, identified 237 unique variants, and annotated a total of 12,676 associated phenotypic terms. The most common features were ataxia, hemiplegic migraine, episodic ataxia, and global developmental delay. Episodic ataxia was associated with presumed loss-offunction variants, while hypotonia, involuntary movements, and tremor were associated with missense variants. Among 164 individuals with seizures, multiple seizure types and electrographic features were reported, with generalized and focal onset seizures occurring at similar frequencies. Developmental delays were significantly more common in those with seizures, especially when seizure onset occurred prior to 22 months of age. Autistic features were also more common in those with earlier seizure onset, while absence seizures occurred more often when seizures onset after 22 months. The results of this study may have important management and prognostic implications for individuals with a new diagnosis of a CACNA1A-related disorder. Further research incorporating functional data may elucidate more specific genotype-phenotype correlations.