A 4-year-old girl is brought to the pediatric clinic by her mother with a history of infantile spasms controlled on vigabatrin since age 8 months. On examination, you note hypomelanotic macules on her trunk (accentuated under Wood's lamp), facial angiofibromas over the malar regions, and a shagreen patch on the lumbosacral skin. Brain MRI shows multiple cortical tubers and a small subependymal nodule. The inheritance pattern shown as **A** in the diagram best describes the genetic basis of this child's condition. Which of the following statements about this inheritance pattern is most consistent with the clinical presentation in this case?

Question

Accepted Answer

A. The condition shows high penetrance but variable expressivity, explaining why the child's mildly affected mother may have had only skin findings while the child has severe neurological disease. ## Why Option 1 is correct

Tuberous sclerosis complex (TSC) is the prototype autosomal dominant condition with variable expressivity and high penetrance. The anchor **A** in the diagram represents this inheritance pattern. The clinical anchor states that TSC is caused by germline loss-of-function mutations in either TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13.3), with approximately two-thirds of cases being sporadic (de novo) and one-third inherited from a parent who may be only mildly affected. The high penetrance (approaching 100% with detailed phenotyping) means most carriers show some features, but expressivity varies enormously—from cosmetically minor skin findings to disabling epilepsy and renal failure within the same kindred. In this case, the child's severe neurological disease (infantile spasms, cortical tubers) with prominent cutaneous features could coexist with a parent who has only subtle skin manifestations, exemplifying variable expressivity. This is why careful examination of both parents (skin, retinal exam, renal ultrasound, brain MRI) is essential when a child presents, and genetic counselling must emphasize a 50% recurrence risk per offspring.

## Why each distractor is wrong

- **Option 2**: TSC is autosomal dominant, not maternally inherited mitochondrial (which would be represented by **D**). Both parents can be carriers or affected, and paternal transmission is equally common as maternal transmission.
- **Option 3**: TSC is autosomal dominant, not autosomal recessive (which would be represented by **B**). Only one mutated allele is required for clinical manifestation; two mutated alleles would be incompatible with life or would represent a different genetic condition.
- **Option 4**: TSC is not X-linked dominant (which would be represented by **C**). The TSC1 and TSC2 genes are on autosomes (chromosomes 9 and 16, respectively), not on the X chromosome. X-linked inheritance would show a different pattern of male predominance and carrier females.

**High-Yield:** TSC is autosomal dominant with variable expressivity and high penetrance—one mutated allele causes disease, but severity ranges from mild skin findings to severe multisystem involvement, even within families. Two-thirds of cases are de novo; always examine parents carefully.

[cite: Nelson 21e Ch 614; International TSC Consensus 2012]

Answer

B. The condition requires two mutated alleles for clinical manifestation, making it unlikely that both parents are clinically affected

Answer

C. The condition is inherited exclusively through maternal lineage, and the child's father cannot be a carrier or affected individual

Answer

D. The condition is inherited through the X chromosome, which explains the predominance of severe disease in males and milder disease in heterozygous females

Explanation

Why Option 1 is correct

Why each distractor is wrong

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