A cohort of 325 patients with TSC indicated that 257 patients (79%) had de novo disease, whereas 68 patients (21%) were familial.17De novo patients are two times more likely to bear TSC2 variants and simplex patients 3.4 times, whereas TSC1 and TSC2 are equally prevalent in familial patients.18 Explanations for the preponderance of nonfamilial disease include (1) subclinical parental somatic mosaicism, (2) a de novo pathogenic variant occurring in gametes before fertilization, or (3) the affected patient developing somatic mosaicism during early cell divisions in embryogenesis. Here, TSC2 is linked to tuberous sclerosis.