A 3-year-old boy born to unaffected parents presents with overgrowth, macrocephaly with frontal bossing, sparse frontoparietal hair, downslanting palpebral fissures, and mild learning difficulties. Genetic testing confirms a heterozygous NSD1 mutation. The inheritance pattern shown in the pedigree is marked as **A** — autosomal dominant with de novo mutation, unaffected parents, and no consanguinity. Which of the following best explains the recurrence risk for the parents' future children?

Question

Accepted Answer

C. Approximately 1% (germline mosaicism aside), as >95% of Sotos syndrome cases are de novo mutations in unaffected parents. ## Why option 1 is right

Sotos syndrome (cerebral gigantism) is caused by heterozygous loss-of-function mutations or 5q35 microdeletions in NSD1, a histone methyltransferase gene. The inheritance pattern marked **A** — autosomal dominant with de novo (sporadic) mutation and unaffected parents — applies to >95% of cases. In this scenario, the proband's parents are phenotypically and genotypically unaffected; the mutation arose de novo in the germline of one parent. Therefore, the recurrence risk for future siblings is approximately 1% (accounting for rare germline mosaicism), not the 50% risk seen in familial cases with vertical transmission. This low recurrence risk is a critical counselling point for families with de novo Sotos syndrome.

## Why each distractor is wrong

- **Option 2**: Autosomal recessive inheritance (pattern **B** in the diagram) would require consanguineous parents and multiple affected siblings. This proband has unaffected parents, ruling out recessive inheritance and a 25% recurrence risk.
- **Option 3**: A 50% recurrence risk applies only to familial cases where an affected parent carries the mutation and passes it to offspring. Since both parents are unaffected and the mutation is de novo, this risk does not apply.
- **Option 4**: If the mutation were present in all somatic cells of both parents, they would manifest Sotos syndrome phenotype. The parents are unaffected, confirming the mutation is not present in their somatic cells.

**High-Yield:** >95% of Sotos syndrome cases are de novo mutations in unaffected parents; recurrence risk ~1% (germline mosaicism aside); familial cases with 50% risk are rare but follow autosomal dominant pattern with male-to-male transmission.

[cite: Tatton-Brown K, Rahman N — GeneReviews Sotos Syndrome; Kurotaki N et al., Nat Genet 2002]

Answer

A. Approximately 100%, as the mutation is present in all somatic cells of the proband's parents

Answer

B. Approximately 50%, as both parents are obligate carriers of the NSD1 mutation

Answer

D. Approximately 25%, as the condition follows autosomal recessive inheritance in this family

Explanation

Why option 1 is right

Why each distractor is wrong

Practice similar questions