Abstracts

Rationale: Tuberous sclerosis complex (TSC) is a phenotypically heterogenous autosomal dominant epilepsy, neuropsychiatric, and tumoral predisposition disease, occurring due to changes in the TSC1 or TSC2 genes. While in many patients a disease-associated variant in TSC1 or TSC2 can be identified, there have been challenges in linking genotype to phenotype.  

Methods: Using a multicenter retrospective natural history cohort of TSC patients, we aimed to identify TSC patients with homogeneous neurologic disease representation. We also sought to perform analyses of TSC1 and TSC2 variant type and variant position to phenotype, to potentially highlight mechanisms of neurologic disease. All patients with complete phenotype data (N = 947) from the TSC Alliance Natural History Database were included in the study. Using 29 clinical features of TSC occurring with a frequency of at least 5%, we performed unsupervised logistic principal components analysis to identify neurologic symptom clusters. Genetic data were aggregated and variants were classified by affected gene, exon, and substitution. Genetic features were compared with neurologic symptom cluster, and the occurrence of infantile spasms, focal seizures, neuropsychiatric disorders, or verbal (cognitive) abilities. 

Results: Four reproducible neurologic symptom clusters differentially associated with TSC1 and TSC2, and also associated with variant type and location. Neurologic symptom clusters revealed a trend toward mutual exclusivity among patients with infantile spasms, neuropsychiatric comorbidities, and subependymal giant cell astrocytomas. Across the 762 patients with genomic data, 221 (29%) had variants in TSC1 and 541 (71%) had variants in TSC2. Insertions were more commonly observed in patients with TSC1 variants than TSC2 variants (10.4% vs. 4.6%, p = 0.005, Fisher’s exact test). In analyses of variant location and phenotype, we identified associations between TSC2 variants in exons 17, 34, and 41 and infantile spasms, as well as the neuropsychiatric phenotype with TSC2 variants in exon 40 and TSC1 variants in exons 8, 13, and 14.  

Conclusions: We identified four neurologic symptom clusters in tuberous sclerosis complex and describe how they associate with genotype, providing the basis for future studies connecting genotype to phenotype in TSC. 

Funding: The authors acknowledge the support of TSC Alliance who maintains TSCNHD and of the TSC clinics who contribute to the TSCNHD. The views expressed in this abstract are those of the authors and do not necessarily reflect the opinion of the TSC Alliance. All authors note no funding toward this project.