Neurofibromatosis Type I (NF1) is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

/pdf/genetic-analyses-of-the-nf1-gene-in-turkish-zmnjbi7zp9.pdf

Genetic Analyses of the NF1 Gene in Turkish Neurofibromatosis Type I Patients and Definition of three Novel Variants.

// Debao Liu 1, 2, * , Yueying Zhang 3, * , Yan Li 4 and Kaixi Fan 1 1 Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China 2 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China 3 Department of Pathology and Pathophysiology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China 4 Department of Central Laboratory, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China * These authors have contributed equally to this work Correspondence to: Kaixi Fan, email: fankaixiyx@sina.com Keywords: gastric cancer, neurofibromatosis type I, TNM stage, immunohistochemistry, prognosis Received: December 02, 2016     Accepted: July 06, 2017     Published: August 03, 2017 ABSTRACT We investigated whether the Neurofibromatosis type-1 ( NF1 ) gene was of prognostic relevance to gastric cancer (GC) patients. Immunohistochemical staining of 160 matched GC tumor and adjacent normal tissue samples showed that 58.1% (93/160) of GC samples were NF1-positive as compared to 94.4% (151/160) of normal tissue samples (χ 2 =58.05, P 0.05). Kaplan-Meier analysis revealed that negative or low NF1 were associated with poor overall survival (OS) in gastric cancer patients ( P <0.001). Further univariate and multivariate cox regression analysis also showed that NF1 expression was an independent risk factor of survival of GC patients. These data show that NF1 has prognostic relevance to clinical outcomes in gastric cancer patients.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=19876&path%5B%5D=63439

Neurofibromatosis type-1 is a prognostic indicator in human gastric carcinoma.

Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased the number of detected variants. However, the correlation of these variants with the clinic remains poorly understood. In this study, we analyzed 4610 germinal NF1 variants annotated in ClinVar and determined on exon level the mutational spectrum and potential pathogenic regions. Then, a binomial and sliding windows test using 783 benign and 938 pathogenic NF1 variants were analyzed against functional and structural regions of neurofibromin. The distribution of synonymous, missense, and frameshift variants are statistically significant in certain regions of neurofibromin suggesting that the type of variant and its associated phenotype may depend on protein disorder. Indeed, there is a negative correlation between the pathogenic fraction prediction and the disorder data, suggesting that the higher an intrinsically disordered region is, the lower the pathogenic fraction is and vice versa. Most pathogenic variants are associated to NF1 and our analysis suggests that GRD, CSRD, TBD, and Armadillo1 domains are hotspots in neurofibromin. Knowledge about NF1 genotype–phenotype correlations can provide prognostic guidance and aid in organ-specific surveillance.

/pdf/identification-of-germinal-neurofibromin-hotspots-2ame45u7.pdf

Identification of Germinal Neurofibromin Hotspots

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. This retrospective study aims to evaluate the clinical manifestations and brain magnetic resonance images (MRI) analysis in 60 genetically confirmed NF1 patients. The results of next-generation sequencing (NGS), Sanger sequencing, and MLPA of NF1 gene were evaluated. A total of 54 different variants were identified. Fourteen out of them were novel variants (25.9%). Patients who complied with NIH criteria had most frequently frameshift variants (11/32 patients), and those with only CALMs had missense variants (9/28 patients). Neurofibromatosis type 1 bright objects (NBOs) on T2-weighted MRI were detected in 42 patients (42/56; 75%). These brain lesions were detected mostly in basal ganglia and in cerebellar vermis. NBOs were detected more in the patients who complied with NIH criteria (80.6%) compared to those who were only CALMs (68%). While frameshift variants (33.3%) were the most common type variants in the patients who had NBOs, the most common variants were splicing (35.7%) and missense (35.7%) variants in the patients whose MRIs were normal. Frameshift variants (11/28 patients; 39.3%) were the most common in the patients with more than one brain locus involvement. Therefore, we consider that frameshift variants may be associated with increased incidence of NBOs and involvement of more than one brain locus. In addition, NBOs may occur less frequently in the patients with splicing variants. To our knowledge, this is the first study evaluated the relationship between NF1 gene variants and NBOs. Future studies may help us understand the etiology of NBOs.

Evaluation of clinical findings and neurofibromatosis type 1 bright objects on brain magnetic resonance images of 60 Turkish patients with NF1 gene variants

We analyzed the clinical features and NF1 gene mutation in a Chinese pedigree of neurofibromatosis type 1 (NF1). Three members of this family were NF1 patients presenting with different clinical phenotypes and the others were asymptomatic. Exons of NF1 were amplified by polymerase chain reaction, sequenced, compared with a reference database. One novel NF1 frame-shift mutation c.703_704delTA, which resulted in a premature stop signal at codon 720 and the synthesis of truncated, was revealed. This mutation segregated with the NF1 members is likely responsible for the pathogenesis of NF1 in the family.

A novel NF1 frame-shift mutation c.703_704delTA in a Chinese pedigree with neurofibromatosis type 1

Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China.

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Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China.