End of a diagnostic odyssey: the added value of multi-tissue analysis in the identification of mosaicism in tumour predisposition syndromes.

Multi-tissue NGS analysis to detect constitutional low allele-fraction variants (VAF 1–7%) undetectable in blood DNA alone

Three patients with strong clinical suspicion of tumor predisposition syndromes (VHL, NF1, NF2) without detectable pathogenic variant in blood underwent multi-tissue NGS analysis (affected tissues). A recurrent pathogenic variant at low allele fraction (VAF 1–7%) was identified in each case, retrospectively confirming low-grade mosaicism. This multi-tissue strategy is an effective approach to end the diagnostic odyssey in patients with strong clinical suspicion and initially negative blood testing.

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These three cases illustrate an important limitation of standard NGS: sensitivity on blood DNA is insufficient for very low-grade mosaicism. Multi-tissue analysis should be systematically considered in patients with a clinical presentation suggestive of hereditary tumor predisposition syndrome without identified variant, especially when multiple characteristic tumors are present. This should be integrated into the diagnostic algorithms of specialized centers.

Clinical impact: 2/3 · Evidence strength: 1/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 1/1 → Total: 6/10