Phenotypic clustering in tuberous sclerosis complex reveals four distinct disease trajectories

Abstract Tuberous sclerosis complex (TSC) is a phenotypically heterogeneous autosomal dominant epilepsy, neuropsychiatric, and tumoral predisposition disease, occurring due to germline variants in the TSC1 or TSC2 genes. Despite an improving understanding of the varied phenotypes TSC may present with, there remains an incomplete understanding of the disease trajectory and genotype-phenotype relationship in this disorder. We sought to examine whether an unbiased clustering approach could uncover subgroups of disease trajectories in TSC and enhance understanding of genotype-phenotype correlation. In this observational, prospective, multicentre natural history cohort of patients with confirmed diagnosis of TSC (TSC Alliance Natural History Database), data collected from 2006 - 2022 was used to identify groups of co-occurring phenotypes. This was a multicentre study involving 18 TSC clinical network centres in the US. 947 individuals were included, all of whom had a clinical diagnosis of tuberous sclerosis complex. Each patient was required to have complete characterization of 29 phenotype features associated with TSC. The primary outcomes were consensus clusters of clinical features defining subgroups of patients with TSC and their association with genotype. 947 individuals (50% male) across the TSC Alliance Natural History Database were included in this study, and 29 clinical features were used to define clusters of phenotypes to define disease trajectories. Four reproducible and distinct disease subgroups were identified: angiomyolipoma-predominant TSC (cluster 1), TSC with infantile spasms (cluster 2), neuropsychiatric TSC (cluster 3), and a milder phenotype of TSC (cluster 4). Variants in the rho domain of hamartin and the TSC1 binding domain of tuberin preferentially associated with cluster 1, with increased likelihood of angiomyolipomas, dermatologic findings, and subependymal giant cell astrocytoma. Four distinct disease subgroups exist in TSC and differentially associate with variant location, informing deep genotype-phenotype correlation in TSC with potential impact in personalizing disease surveillance, treatment, and clinical trial endpoint choice. Additional prospective data are needed to confirm these findings.