A 3-year-old boy presents with a 6-month history of infantile spasms and developmental delay. On examination, he has multiple hypomelanotic macules on his trunk and facial angiofibromas. Brain MRI shows cortical dysplasias and subependymal nodules. Genetic testing confirms a de novo TSC2 mutation. The inheritance pattern marked **B** in the pedigree diagram indicates this is an autosomal dominant disorder with a high de novo mutation rate. Which of the following best explains why approximately two-thirds of tuberous sclerosis cases present as sporadic (de novo) mutations rather than inherited from an affected parent?

Question

Accepted Answer

A. TSC1 and TSC2 mutations have exceptionally high spontaneous mutation rates, and affected individuals often have reduced reproductive fitness due to severe neurological and systemic manifestations. ## Why "TSC1 and TSC2 mutations have exceptionally high spontaneous mutation rates, and affected individuals often have reduced reproductive fitness due to severe neurological and systemic manifestations" is right

Tuberous sclerosis complex is an autosomal dominant disorder caused by loss-of-function mutations in TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13.3). Approximately 2/3 of cases are sporadic (de novo mutations), reflecting the high spontaneous mutation rate of these genes. Additionally, many affected individuals have significant neurological morbidity (80–90% develop epilepsy, ~50% have intellectual disability, ~40–50% have autism spectrum disorder), which reduces reproductive fitness and limits vertical transmission. This combination of high de novo mutation rate and reduced reproductive success in affected individuals explains the predominance of sporadic cases. (International TSC Consensus 2021)

## Why each distractor is wrong

- **"TSC is inherited in an autosomal recessive pattern..."**: TSC is definitively autosomal dominant, not recessive. A single mutated allele is sufficient to cause disease with high penetrance. The pedigree diagram explicitly marks **B** as autosomal dominant.
- **"The TSC1 and TSC2 genes are located on the X chromosome..."**: TSC1 is on chromosome 9q34 and TSC2 is on chromosome 16p13.3—both autosomal, not X-linked. X-linked inheritance would show a different pattern and is not consistent with the epidemiology or genetics of TSC.
- **"TSC mutations are exclusively mitochondrial..."**: TSC is not a mitochondrial disorder. Mitochondrial inheritance would show maternal-only transmission and would not produce the observed pedigree pattern. TSC is caused by nuclear gene mutations in TSC1 and TSC2.

**High-Yield:** ~2/3 of TSC cases are de novo mutations due to high spontaneous mutation rate + reduced reproductive fitness in affected individuals; TSC is autosomal dominant with high penetrance but variable expressivity.

[cite: International TSC Consensus 2021; EXIST trials]

Answer

B. TSC mutations are exclusively mitochondrial and therefore show maternal inheritance with variable penetrance

Answer

C. TSC is inherited in an autosomal recessive pattern, so most cases appear sporadic when only one parent carries a mutation

Answer

D. The TSC1 and TSC2 genes are located on the X chromosome, making inheritance patterns unpredictable in males

Explanation

Why "TSC1 and TSC2 mutations have exceptionally high spontaneous mutation rates, and affected individuals often have reduced reproductive fitness due to severe neurological and systemic manifestations" is right

Why each distractor is wrong

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