High-Yield DNA-Based Neurofibromatosis Type 1 Diagnostics Reveal Population-Specific Mutation Landscape in 1917...

Area of Science:

• Genetics
• Molecular Biology
• Clinical Diagnostics

Background:

• Neurofibromatosis type 1 (NF1) is a prevalent autosomal dominant disorder with significant genetic diversity.
• Current RNA-based diagnostic assays for NF1 are sensitive but limited by cost and complexity for routine clinical use.

Purpose of the Study:

• To evaluate the diagnostic yield and efficiency of a tiered, DNA-only approach for Neurofibromatosis type 1 (NF1) in a large Korean cohort.
• To characterize the mutational landscape of NF1 in the Korean population and identify potential genotype-phenotype correlations.

Main Methods:

• A stepwise diagnostic workflow involving targeted gene sequencing, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing was applied to 1,917 individuals with suspected NF1.
• Analysis focused on DNA-derived variants, including copy-number variations and single nucleotide variants.
• Variant data were compared with existing European cohort data to identify population-specific differences.

Main Results:

• The tiered DNA-only strategy achieved a cumulative diagnostic yield of 81.6% for NF1.
• Truncating variants were the most common pathogenic variants (79.0%), and 81.4% of identified variants were private to the cohort.
• Population-specific differences in variant frequency were observed compared to European cohorts, with certain known pathogenic variants being rare.

Conclusions:

• A stepwise, DNA-only diagnostic approach is highly effective and scalable for routine Neurofibromatosis type 1 (NF1) diagnosis.
• This strategy provides a robust and practical alternative to RNA-based methods in clinical settings.
• The study delineates a Korean-specific NF1 mutational landscape, highlighting the importance of population-specific genetic data.