The genetic basis of the disorder is [[mutation]]s in the [[TSC1]] or [[TSC2]] gene, which leads to overactivation of the mammalian target of rapamycin ([[mTOR]]) protein complex and results in the development of benign tumors in different body systems such as the brain, skin, lungs, and kidney. 

Autosomal dominant inheritance; however, spontaneous mutation accounts for the majority of cases.

[[Focal cortical dysplasia]] (FCD) is a localized [[cortical malformation]] and considerable morphological overlap exists between [[Focal cortical dysplasia type II B]] (FCD IIB) and neurological lesions associated with [[Tuberous sclerosis complex]] (TSC). Abnormal [[mTOR pathway]] secondary to somatic [[mTOR]] [[mutation]] and TSC gene mutation linked to PI3K/AKT/mTOR pathway have supported the hypothesis of common pathogenesis involved.
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Two distinct tumor suppressor genes have been identified: the [[TSC1]] gene (located on chromosome 9q34) codes for TSC1 (AKA hamartin), and the [[TSC2]] gene (on chromosome 16p13.3) codes for TSC2 (tuberin). Only 1 gene needs to be affected to develop TSC. These proteins work together to inhibit the activation of rapamycin (mTOR).
Genetic counseling for unaffected parents with one affected child: 1–2% chance of recurrence
((European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315.))
((van Slegtenhorst M, deHoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808.)).