TUBEROUS SCLEROSIS

GENETICS

PATTERN OF INHERITANCE

• In two thirds of cases: de novo acquired gene abnormality, these may be somatic pathogenic variants or germline pathogenic variants
• In one third of cases: familial inheritance - autosomal dominant with high penetrance

KNOWN GENES

Gene abnormalities in TSC1 (on 9q34, encoding hamartin) or TSC2 (on 16p13, encoding tuberin) genes are responsible for the majority of tuberous sclerosis cases. Hamartin and tuberin form a complex that is required for normal function of the mTOR pathway. The TSC1 or TSC2 gene abnormality is detectable in blood in most individuals with tuberous sclerosis. Usually individuals have one copy of the abnormal gene, resulting in reduced normal hamartin/tuberin production initially. Over time, a second acquired gene abnormality may occur in the other copy of the TSC gene, resulting in further reduction in normal hamartin/tuberin production and loss of regulation of cell growth in those cells with two abnormal TSC genes. Up to 10-25% of patients may not have a TSC1/2 gene abnormality found in blood, these individuals are likely to still have a TSC1 or TSC2 gene abnormality, but present only in a small percentage of blood cells, or present in other cells (such as brain or kidney cells) in the body.

FAMILY HISTORY

May be present, a history of seizures/epilepsy or skin or renal disease in family members should be sought.