This panel includes the two genes that have been associated with tuberous sclerosis complex (TSC). This condition has an estimated prevalence of 1 in 6,000-10,000 individuals, and the clinical features associated with TSC1 versus TSC2 pathogenic variants are indistinguishable . Skin findings are one of the most consistent clinical features, and these can include the following: hypopigmented macules such as ash-leaf spots or confetti lesions, facial angiofibromas, shagreen patches, and ungual fibromas. Neurological findings typically have the most significant impact on health and development with tumors of the central nervous system being a major contributor to morbidity and mortality in TSC. Seizures are present in up to 80% of affected individuals, and brain imaging may reveal the presence of cortical tubers as well as subependymal nodules (SEN) or giant cell astrocytoma (SEGA). A majority of patients have intellectual disability to varying degrees, and autism spectrum disorders, ADHD, behavioral issues, and sleep problems may also occur. Additional signs include cardiac rhabdomyomas, retinal hamartomas, renal cysts, renal angiomyolipoma which is associated with the risk of malignancy, and lymphangioleiomyomatosis, particularly in adult women with TSC. Routine surveillance is recommended across multiple body systems to allow for early detection and potential intervention for some of these concerns.
Tuberous sclerosis is considered to be an autosomal dominant disorder, but a majority of cases are due to de novo mutations or germline mosaicism. New mutations occur at a higher rate in TSC1 than TSC2. Significant variability in the degree of expression is a major feature of this condition, even within the same family. In general, pathogenic variants in TSC2 are associated with a more severe phenotype than pathogenic TSC1 alterations.