A 3-year-old boy is brought to the pediatric clinic with developmental delay, coarse facial features, and hypoplasia of the fifth digit nails. His parents are healthy and unrelated, with no family history of similar conditions. Genetic testing confirms a heterozygous de novo mutation in ARID1B. The inheritance pattern marked **A** in the pedigree diagram shows the characteristic presentation of Coffin-Siris Syndrome. Which of the following best describes the inheritance pattern and recurrence risk for this family?
A. Autosomal recessive with consanguineous parents; recurrence risk to future siblings 25%
B. Autosomal dominant with de novo mutation; recurrence risk to future siblings <1% unless germline mosaicism is present
C. Autosomal dominant with paternal transmission; recurrence risk to future offspring 50% if the father is affected
D. X-linked recessive with carrier mother; recurrence risk to future sons 50%
Explanation
Why option 1 is correct
Coffin-Siris Syndrome (CSS) caused by BAF complex gene mutations (most commonly ARID1B) follows an autosomal dominant inheritance pattern. Critically, virtually all cases are de novo mutations — the affected proband is the only family member with the condition, and both parents are healthy and unrelated (non-consanguineous). This is the hallmark of CSS inheritance. The recurrence risk to unaffected parents' future children is less than 1% in the absence of germline mosaicism, because the parents carry no pathogenic variant. The affected individual's own offspring would have a 50% risk of inheriting the mutation, though most affected individuals do not reproduce. The pedigree pattern marked A — sporadic appearance with healthy parents and unaffected siblings — is pathognomonic for autosomal dominant de novo inheritance and distinguishes CSS from autosomal recessive syndromes.
Why each distractor is wrong
Option 2 (Autosomal recessive): Autosomal recessive inheritance requires consanguineous parents and affected siblings, not healthy unrelated parents with a single affected child. The 25% recurrence risk applies only to autosomal recessive conditions. CSS is autosomal dominant, not recessive.
Option 3 (X-linked recessive): X-linked recessive inheritance would show a carrier mother with affected sons and no paternal-to-son transmission. CSS is autosomal, not X-linked. Additionally, males and females are equally affected in CSS, which is inconsistent with X-linked inheritance.
Option 4 (Paternal transmission with 50% risk): While affected individuals' offspring do have a 50% recurrence risk, this option incorrectly implies the father is affected. In this case, the father is healthy and unaffected; the mutation arose de novo in the proband. The 50% risk applies to the affected proband's future children, not the unaffected parents' future children.
High-YieldNEET PG
Coffin-Siris Syndrome = autosomal dominant BAF complex gene mutation (ARID1B most common) with virtually all cases being de novo; healthy parents + affected child = <1% recurrence risk to siblings.
Tsurusaki Y et al., Nat Genet 2012; Schrier Vergano S, GeneReviews — Coffin-Siris Syndrome
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