Diagnóstico de neurofibromatosis tipo 1 de alto rendimiento basado en ADN revela un panorama de mutaciones específico...

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with extensive allelic heterogeneity. Although RNA-based assays can increase sensitivity, their cost and complexity limit their routine use. We evaluated a DNA-only tiered diagnostic approach in 1,917 unrelated Korean individuals with clinically suspected NF1. The process began with targeted sequencing of blood-derived genomic DNA, followed by reflex MLPA for copy-number variants and lesional tissue test for suspected mosaicism. Initial targeted sequencing of NF1 gene established a diagnostic yield of 74.0%. The addition of reflex MLPA and tissue testing increased the cumulative yield to 79.2%. Subsequent post-report variant reclassification and whole-genome sequencing further raised the overall diagnostic yield to 81.6%. Among 901 distinct pathogenic variants identified-81.4% of which were private-truncating variants were predominant (79.0%). Notably, several variants enriched in European cohorts and with established genotype-phenotype correlations (e.g., p.Arg1809Cys, p.Met992del, p.Arg1276Gln) were rare in our cohort, highlighting population-specific differences. Individuals with large deletions were referred at younger ages, suggesting potential genotype-phenotype associations. These data demonstrate that a stepwise, DNA-only strategy delivers high yield and scalability for routine NF1 diagnostics, while delineating a Korean-specific mutational landscape. This practical workflow offers a robust alternative to RNA-based approaches in real-world clinical settings.