Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort.

Reduced penetrance in unselected population

From 500,000 UK Biobank adults, penetrance of pathogenic/likely pathogenic COL1A1 and COL1A2 variants was 40.7% and 21.3% respectively. Among 115 carriers, 60% of COL1A1 and 79% of COL1A2 carriers had no OI diagnosis. For COL1A1 truncating variants, penetrance reached 73.1%, and 90% had reduced circulating COL1A1 protein, suggesting a subclinical phenotype. Current ClinVar assertions may overstate OI risk for missense variants in population screening settings.

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Consistent with the concurrent TSC1/TSC2 penetrance data (EJHG 2026, same group), OI population penetrance is systematically lower than clinical estimates. The distinction between truncating (73% penetrance) and missense variants (very low) is essential for newborn screening strategy and ACMG variant interpretation.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 7/10