J Genet Med.  2024 Jun;21(1):22-30. 10.5734/JGM.2024.21.1.22.

Mutation spectrum of NF1 gene in Korean unrelated patients with neurofibromatosis 1: Six novel pathogenic variants

• Han SH
• Kang EJ
• Yang M
• Kim S
• Lee SG
• Lee EH

• KMID: 2557481
• DOI: http://doi.org/10.5734/JGM.2024.21.1.22

Abstract

Purpose
Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant diseases caused by heterozygous mutation in the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of a high number of partial pseudogenes, and the great variety of mutations. We aimed to study the mutation spectrum of NF1 gene in Korean patients with NF1.
Materials and Methods
We have analyzed total 69 unrelated patients who were clinically diagnosed with NF1. PCR and sequencing of the NF1 gene was performed in all unrelated index patients. Additionally, multiplex ligation-dependent probe amplification (MLPA) test of the NF1 and SPRED1 gene analysis (sequencing and MLPA test) were performed in patients with negative results from NF1 gene sequencing analysis.
Results
Fifty-five different variants were identified in 60 individuals, including six novel variants. The mutations included 36 single base substitutions (15 missense and 21 nonsense), eight splicing mutations, 13 small insertion or deletions, and three gross deletions. Most pathogenic variants were unique. The mutations were evenly distributed across exon one through 58 of NF1, and no mutational hot spots were found. When fulfilling the National Institutes of Health criterion for the clinical diagnosis of NF1, the detection rate was 84.1%. Cafe-au-lait macules were observed in all patients with NF1 mutations. There is no clear relationship between specific mutations and clinical features.
Conclusion
This study revealed a wide spectrum and genetic basis of patients with NF1 in Korea. Our results aim to contribute genetic management and counseling.

Keyword

Neurofibromatosis 1; SPRED1; Mutations; Genotype-phenotype correlation