Likelihood of TSC1(NM_001406592.1):c.-144+1G>C Mutation Leading to Tuberous Sclerosis Complex
The TSC1 gene mutation c.-144+1G>C has a high likelihood of causing Tuberous Sclerosis Complex (TSC) as it affects a splice site in the TSC1 gene, which is one of the two genes definitively associated with TSC development. 1
Understanding TSC and Its Genetic Basis
- TSC is an autosomal dominant disorder characterized by hamartomas in multiple organ systems including brain, kidneys, heart, skin, and lungs 1
- TSC is caused by mutations in either the TSC1 gene (chromosome 9q34) or TSC2 gene (chromosome 16p13.3) that inactivate their tumor-suppressive function 1, 2
- The TSC1 gene encodes hamartin, a 130-kilodalton protein that functions as a tumor suppressor 2
- TSC1/TSC2 genes inhibit the mTOR complex; when mutated, they lead to activation of mTORC1 and dysregulation of downstream cellular pathways including cell growth and proliferation 3
Analysis of the Specific Mutation
- The mutation c.-144+1G>C affects a splice site (indicated by the +1 position), which typically disrupts normal RNA splicing 1
- Splice site mutations are generally considered pathogenic as they often lead to abnormal protein production or nonsense-mediated decay 1
- This specific mutation occurs in the 5' untranslated region of the TSC1 gene (indicated by the negative position number), which can affect gene expression and regulation 1
Evidence Supporting Pathogenicity
- Mutations in TSC1, including splice site mutations, have been consistently associated with TSC development 2
- 10-15% of patients meeting clinical criteria for TSC have no identifiable mutation in TSC1 or TSC2 genes, often due to mosaicism, but conversely this means 85-90% of cases are explained by mutations in these genes 1
- Molecular evaluation has demonstrated that TSC gene mutations lead to activation of mTORC1 and dysregulation of downstream cellular pathways 3
- Large deletions at the TSC1 locus have been reported in families with TSC, indicating that various mutation types in this gene can cause the disease 4
Clinical Implications
- TSC2 mutations generally cause more severe disease than TSC1 mutations, particularly regarding neurological manifestations and kidney involvement 1
- Patients with TSC1 mutations may still develop the full spectrum of TSC manifestations, including:
- Neurological: cortical tubers, subependymal nodules, seizures, developmental delay 1, 5
- Renal: angiomyolipomas (70-80% of patients), cystic kidney disease (50%), renal cell carcinoma (3-5%) 1
- Cardiac: rhabdomyomas in about two-thirds of newborns with TSC 1
- Skin: facial angiofibromata and other skin lesions in nearly 100% of individuals 1
Diagnostic Approach
- Genetic testing is recommended for all patients with definite or suspected TSC 1
- High-sensitivity genetic analysis is recommended if standard testing is negative in patients with clinical features of TSC, as mosaicism is common 1
- Clinical diagnostic criteria involve combinations of major and minor criteria, including cortical dysplasias, subependymal nodules, and characteristic skin lesions 1
Management Considerations
- A coordinated multidisciplinary approach involving specialists from neurology, nephrology, pulmonology, dermatology, and other disciplines is essential 1
- Regular surveillance is necessary:
Important Caveats
- Even with identical TSC2 mutations, there can be variability in TSC symptoms among patients, suggesting that other genetic or environmental factors influence disease expression 7
- Parents of a child with seemingly sporadic TSC have a 1-2% risk of having another affected child due to possible germline mosaicism 1
- Genetic counseling is strongly recommended for all patients with TSC who are considering having children 1