Germline NF2 variant position constrains somatic second hits and determines clinical severity in Neurofibromatosis Type 2-related schwannomatosis

Clinical characteristics and variant spectrum of NF1 in Chinese patients with neurofibromatosis type 1: a cross-sectional study

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Among 847 patients, the median age was 23 years, 27.5% had a family history of NF1, and more than 90% were younger than 40 years. Café-au-lait macules, neurofibromas, and plexiform neurofibromas were observed in 98.3%, 70.7%, and 20.9% of patients, respectively. Younger age, lower neurofibroma burden, and absence of learning difficulties were associated with DNB-defined mild classification. Among 211 genetically tested patients, pathogenic/likely pathogenic NF1 variants were identified in 182 patients, 11 carried NF1 variants of uncertain significance, and 18 had no reportable NF1 variant. In total, 152 distinct NF1 variants were identified, including 45 novel sites. Transcript-level analysis showed regional variation in reportable nucleotide-level NF1 variants, with relatively higher variant density around exons 10–15 and 44–49. Comparison with ClinVar pathogenic/likely pathogenic NF1 variants showed no significant window-level difference after multiple-testing correction. This cross-sectional study summarizes the clinical and genetic features of Chinese patients with NF1 and expands the known NF1 variant spectrum in this population. Transcript-level analysis showed regional variation in reportable NF1 variants, broadly paralleling the ClinVar pathogenic/likely pathogenic NF1 variant distribution. These findings provide a basis for future longitudinal studies to validate clinically meaningful genotype–phenotype relationships in NF1.

Phenotypic and genotypic characteristics of pediatric patients with neurofibromatosis type 1: a 12-year single-center cohort study.

Case Report: Clinical and molecular genetic analysis of a patient with coexisting complete androgen insensitivity syndrome and neurofibromatosis type 1 and 15pstk + polymorphism

This is the first report of concurrent CAIS and NF1, which enriches and expands the genotypic and phenotypic spectra of both disorders.

Clinical Phenotypic Spectrum and Multisystem Burden in Neurofibromatosis Type 1: A Retrospective Regional Cohort Study

Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder characterized by marked phenotypic heterogeneity. This study aimed to describe the clinical spectrum and multisystem burden of NF1 in a regional retrospective cohort. Methods: We retrospectively analyzed 77 unique patients with NF1 after removal of duplicate records. Demographic characteristics, cutaneous manifestations, extracutaneous involvement, therapeutic interventions, and disease evolution were evaluated. An exploratory multisystem burden score was calculated using six extracutaneous clinical domains. Results: Café-au-lait macules were present in all patients, axillary/inguinal freckling in 93.5%, cutaneous neurofibromas in 63.6%, and plexiform tumors in 28.6%. Psychiatric/behavioral (67.5%), skeletal (57.1%), ophthalmological (51.9%), and neurological (45.5%) involvement were common. More than half of the cohort had involvement of at least three extracutaneous domains. Plexiform tumors were more common in patients with progressive or unfavorable disease compared to those with stationary disease. Progressive or unfavorable evolution was associated with a higher frequency of plexiform tumors. Therapeutic interventions were reported descriptively. Conclusions: NF1 showed substantial multisystem involvement beyond its characteristic cutaneous manifestations. Plexiform tumors were associated with a more complex clinical course. The proposed exploratory multisystem burden score may facilitate descriptive assessment of disease breadth but requires prospective validation.

Clinical and genetic features of syndromic craniosynostosis in 18 Chinese probands: novel candidate genes and phenotypes of known pathogenic genes

The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms in craniosynostosis.

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.