Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.

Reduced penetrance in unselected population

Genome sequencing data from 900,000 adults (UK Biobank and All of Us) revealed that 54% of carriers of (likely) pathogenic TSC1/TSC2 variants have no recorded TSC diagnosis, despite extensive longitudinal healthcare data (median age ≥55 years). Apparent penetrance was 46.6% for TSC1 in both cohorts and 27.8–66.7% for TSC2. These findings directly challenge the assumption of near-complete penetrance derived from clinically ascertained cohorts, with major implications for genomic newborn screening pilots.

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These data demonstrate that TSC penetrance in the general population is far below the 95–100% reported in clinical cohorts. For genomic newborn screening, a P/LP TSC1/2 variant identified at birth does not reliably predict clinical expression. Current ClinVar assertions derived from clinical cohorts warrant re-evaluation.

Clinical impact: 2/3 · Evidence quality: 3/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 8/10