Parents lose a first infant who dies shortly after birth from multiple fractures sustained in utero, blue sclerae, and radiographic crumpled long bones; lethal osteogenesis imperfecta type II is diagnosed. Neither parent has any stigmata of osteogenesis imperfecta, and sequencing of the infant shows a de novo COL1A1 missense variant. The parents ask their risk of recurrence in the next pregnancy. The best answer cites:

• A About a 6 to 7 percent recurrence risk from germline mosaicism in one parent ✓
• B No increased risk, since the variant arose de novo in the child
• C A 50 percent risk, since lethal type II is an autosomal dominant condition
• D A 25 percent risk, since type II collagen disease can be autosomal recessive

Explanation

Although most lethal osteogenesis imperfecta type II cases arise from a de novo COL1B1 mutation, clinically unaffected parents can harbor the same variant in a subset of their germ cells (gonadal or germline mosaicism), which standard blood testing misses. Empiric recurrence risk is therefore quoted around 6 to 7 percent, not negligible. Type II is autosomal dominant, so neither 25 nor 50 percent applies to two unaffected parents, and dismissing all risk is unsafe counselling.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.