Lab Med Online.  2021 Jan;11(1):17-24. 10.47429/lmo.2021.11.1.17.

NF1 Variant Spectrum in Korean Patients with Neurofibromatosis Type 1 Disorder

• Kang H
• Lee J
• Park J
• Yim J
• Chae H
• Kim Y
• Kim M

• KMID: 2525776
• DOI: http://doi.org/10.47429/lmo.2021.11.1.17

Abstract

Background
Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, and many different variants in the NF1 gene have been observed. The aim of this study was to investigate the genetic variant spectrum of NF1patients in Korea.
Methods
A total of 462 cases were enrolled for NF1 analysis at Seoul St. Mary’s Hospital. NF1 was analyzed through Sanger sequencing of messenger RNA (mRNA) and genomic DNA (gDNA), and/or multiplex ligation-dependent probe amplification (MLPA) analysis.
Results
We identified 231 types of NF1 variants in 303 out of the 462 patients (65.6%). Of these, 217 variants were classified as pathogenic or likely pathogenic, and 48.4% (N = 106) of these were novel changes. Truncating variants encompassing frameshift and nonsense variants were most commonly observed (135 types of variants in 177 patients), followed by splicing defect variants (39 types in 42 patients) and missense variants (36 types in 44 patients). There were 8 distinctive large deletions in 25 patients, detected via MLPA analysis. Interestingly, 4 cases showed aberrant transcripts that were identified through mRNA Sanger sequencing. The frequency of NF1 mutation detected was significantly higher according to the number of satisfying National Institutes of Health (NIH) diagnostic criteria.
Conclusions
This study revealed a wide spectrum of NF1 variants in Korean NF1 patients. A comprehensive analytical strategy that combines mRNA and gDNA analyses and MLPA is required to detect sequence variants. Additionally, it is important to define the effect of newly detected variants on the clinical course.

Keyword

Neurofibromatosis 1; NF1; Variant spectrum; mRNA; gDNA; MLPA

Figure

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  Fig. 1 Identified NF1 variant spectrum and location. At the midline of the figure, the involved exons and/or introns of the NF1 gene are listed. Each block upward the midline represents one variation. Different kinds of variations are shown in different colors as indicated in the category above the chart. Large deletions are indicated by the green rectangle at the bottom of the midline. Here, each variant is displayed in the vertical direction. The different horizontal length of each rectangle indicates the deleted scope of each individual variant.

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  Fig. 2 Flow chart showing the NF1 gene analysis according to the clinical findings of enrolled patients. NIH, National Institutes of Health; Sequencing, Sanger sequencing of mRNA and gDNA; MLPA, multiplex ligation-dependent probe amplification.

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