Inheritance Pattern of Tuberous Sclerosis Complex (TSC)

Tuberous sclerosis complex is inherited in an autosomal dominant manner with complete penetrance but variable expressivity. 1

Genetic Basis

TSC is caused by inactivating pathogenic variants in either of two genes:

Autosomal dominant transmission: Only one copy of the mutated gene is needed to cause the disease 1
Complete penetrance: All individuals with a pathogenic TSC1 or TSC2 variant will develop some disease features 1
Variable expressivity: Disease severity varies considerably, even within the same family 1
De novo mutations: Approximately two-thirds of cases are sporadic (not inherited from parents) 2

TSC2 mutations are more common overall, especially in sporadic cases 2
TSC1 mutations are relatively equally distributed among familial cases compared to TSC2, but are underrepresented in sporadic cases 2
Pathogenic variants cannot be identified in 10-15% of clinically diagnosed TSC patients 1

Mosaicism is an important factor in TSC inheritance:

About 25% of first affected family members with contiguous gene deletions show mosaicism 1
Low-level mosaicism may occur in a parent without TSC manifestations 1
Mosaic allele frequency varies across different tissues 1
In ~18% of patients with TSC mosaicism, the pathogenic variant is not detected in blood DNA samples 1

Recurrence risk: For parents of a child with sporadic TSC, the risk in subsequent pregnancies is estimated at ~1-2% due to possible germ cell mosaicism 1
Intrafamilial variability: Genetic counseling should address the high degree of variability in disease severity within families 1
Multiple mutations: Although extremely rare, cases of multiple independent TSC2 mutations within a single family have been reported 3
Different mutations: Family members with clinical TSC may have different genetic etiologies 4

Genotype-phenotype correlation: Patients with TSC2 pathogenic variants often have greater disease severity, including kidney manifestations, compared to those with TSC1 variants 1
Contiguous gene syndrome: Patients with combined deletion of TSC2 and adjacent PKD1 gene have high risk of accelerated cystic kidney disease 1

Genetic diagnosis is recommended for all patients with definite or probable TSC 1
High-sensitivity genetic analysis is recommended if standard testing is negative 1
When a pathogenic variant is identified, expert clinical evaluation of first-degree family members is recommended 1
Genetic counseling is strongly recommended for all TSC patients considering having children 1