Case Report: A somatic NF1 splice-altering variant identified in lesional tissue in peripheral blood-negative segmental facial neurofibromatosis
Background Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by loss-of-function variants in the NF1 gene. Segmental neurofibromatosis represents a rare mosaic form resulting from postzygotic mutations and is often diagnostically challenging due to its localized presentation and variable clinical expressivity. Methods A 25-year-old woman with neurofibromas restricted to the left facial region underwent histopathological evaluation and whole exome sequencing (WES) of lesional tissue. Bioinformatic analyses were used to predict the splicing impact of a novel intronic variant. A minigene splicing assay was performed to experimentally assess transcript-level consequences. Protein structural modeling was used to evaluate the predicted effects on neurofibromin. Results We describe a 25-year-old woman with a segmental distribution of neurofibromas confined to the left facial region, with a progressive mass present for more than two decades. Histopathological and immunohistochemical evaluation of the lesional tissue was performed, followed by WES of paired peripheral blood and affected tissue. WES of the affected tissue identified a novel somatic intronic deletion, NF1 c.7970+4_7970+7del, with a mosaic variant allele fraction of 36.02%. In silico analyses predicted disruption of the canonical donor splice site. A minigene splicing assay experimentally confirmed that the variant causes complete exon 54 skipping, which is predicted to result in a frameshift and premature termination. These findings provide functional evidence that NF1 c.7970+4_7970+7del is a splice-disrupting variant with pathogenic relevance in the context of segmental neurofibromatosis. Conclusion This case expands the spectrum of splice-altering NF1 variants and reveals a previously uncharacterized molecular mechanism underlying segmental neurofibromatosis. The mosaic nature of this somatic variant has important genetic counseling implications, including the possibility of low-level germline involvement. Our results highlight the value of functional validation for intronic variants of uncertain significance and support the potential role of early molecular diagnosis in guiding targeted therapeutic approaches such as MEK inhibition.