What causes tuberous sclerosis?

Neurocutaneous tuberous sclerosis complex (TSC) is a rare, multisystem genetic disorder caused by pathogenic variants—typically loss-of-function mutations—in either the TSC1 gene (encoding hamartin) or the TSC2 gene (encoding tuberin). These two proteins form a critical regulatory complex that inhibits the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. When either protein is dysfunctional due to mutation, mTORC1 becomes constitutively overactive, leading to uncontrolled cellular growth, proliferation, and abnormal differentiation. This results in the hallmark features of TSC: benign hamartomatous lesions in multiple organs—including cortical tubers and subependymal nodules in the brain, cardiac rhabdomyomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis (LAM), and facial angiofibromas.

Approximately two-thirds of cases arise from *de novo* (spontaneous) mutations with no family history, while the remaining one-third are inherited in an autosomal dominant pattern—meaning a single mutated allele is sufficient to cause disease, and each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Importantly, TSC exhibits high penetrance but variable expressivity: all individuals with a confirmed pathogenic variant will manifest some clinical features, but the type, severity, and age of onset can differ widely—even among affected family members.

Genetic testing—including sequencing and deletion/duplication analysis of both TSC1 and TSC2—is recommended for diagnostic confirmation, especially in individuals with atypical or mild presentations. Early molecular diagnosis enables proactive surveillance, timely intervention, and informed family counseling.