Restoration of Normal NF1 Function with Antisense Morpholino Treatment of Recurrent Pathogenic Patient-Specific Variant c.1466A&gt;G; p.Y489C

Awad, Elias K.; Moore, Marc; Liu, Hui; Ciszewski, Lukasz; Lambert, Laura J.; Korf, Bruce R.; Popplewell, Linda; Kesterson, Robert A.; Wallis, Deeann

doi:10.3390/jpm11121320

Cited by 3 publications

(1 citation statement)

References 27 publications

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“…The studies included case analysis and multiple case analysis, mainly for NF1 gene mutation, with various types of mutation, including point mutation, frameshift mutation, splice site mutation, exon mutation, chimeric mutation and de novo mutation. All reported autosomal dominant inheritance [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . DISCUSSION Neurofibromatosis type 1 is a multisystem genetic disease with more than 3000 NF1-related pathogenic variants reported, but pathogenic variants in exon 33 are extremely underrepresented.…”

Section: Resultsmentioning

confidence: 99%

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

X¹,

Wang²,

Wang³

2023

Int J Ophthalmol

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AIM: To detect the pathogenic gene variant in a family with neurofibromatosis type 1 (NF1). METHODS: This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology. After detecting the suspicious pathogenic variant type, the pathogenic variant sites of the patient and the patient’s family members were verified by multiple ligation dependent probe amplification and Sanger sequencing. Sift, polyphen-2, Mutation Taster and GERP++ software were used to predict the pathogenicity of the unknown loci. The clinical data, diagnosis and treatment process of the patients were reviewed. Using the keyword “NF1; frameshift pathogenic variant”, relevant literature was gathered for analysis from Chinese and international databases, with articles dating from the establishment of each database to April 2022. RESULTS: A heterozygous frameshift pathogenic variant of NF1 in exon 33 was detected in the patient. The insertion of adenine in coding region 4486 resulted in the replacement of isoleucine with asparagine in protein 1497. Sanger sequencing validation and segregation analysis were performed, which demonstrated that the NF1 gene was cosegregated with the disease phenotype in this family. This study identified a novel NF1 heterozygous frameshift mutation c.4486dupA (p.I1497Nfs*12). Relevant literature retrieval found 7 Chinese articles and 12 foreign articles. With NF1 gene mutation, mutation types are diverse, including point mutation, frameshift mutation, splice site mutation, exon mutation, chimeric mutation and de novo mutation. Foreign reports are based on autosomal dominant inheritance. CONCLUSION: This study’s results demonstrate that a novel deletion in exon 33 caused NF1 in this Chinese family, expanding the mutational spectrum of the NF1 gene.

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Section: Resultsmentioning

confidence: 99%

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

X¹,

Wang²,

Wang³

2023

Int J Ophthalmol

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Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials

Staedtke,

Anstett,

Bedwell

et al. 2023

Clinical Trials

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Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

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The Number of Surgical Interventions and Specialists Involved in the Management of Patients with Neurofibromatosis Type I: A 25-Year Analysis

Hsu

Denadai

Chang

et al. 2022

JPM

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Objective: In this study, we aim to present a single institution’s 25-year experience of employing a comprehensive multidisciplinary team-based surgical approach for treating patients with NF-1. Summary Background Data: All patients (n = 106) with a confirmed diagnosis of NF-1 who were treated using a multidisciplinary surgical treatment algorithm at Chang Gung Memorial Hospital between 1994 and 2019 were retrospectively enrolled. Patients were categorized into groups according to the anatomy involved (craniofacial and noncraniofacial groups) and the type of clinical presentation (plexiform and cutaneous neurofibromas groups) for comparative analysis. Methods: The number of surgical interventions and number of specialists involved in surgical care were assessed. Results: Most of the patients exhibited craniofacial involvement (69.8%) and a plexiform type of NF-1 (58.5%), as confirmed through histology. A total of 332 surgical interventions (3.1 ± 3.1 procedures per patient) were performed. The number of specialists involved in surgical care of the included patients was 11 (1.6 ± 0.8 specialists per patient). Most of the patients (62.3%) underwent two or more surgical interventions, and 40.6% of the patients received treatment from two or more specialists. No significant differences were observed between the craniofacial and noncraniofacial groups in terms of the average number of surgical interventions (3.3 ± 3.2 vs. 2.7 ± 2.7, respectively) and number of specialists involved (1.7 ± 0.9 vs. 1.4 ± 0.6). Patients with plexiform craniofacial involvement underwent a significantly higher average number of surgical interventions (4.3 ± 3.6 vs. 1.6 ± 1.1; p < 0.001) and received treatment by more specialists (1.9 ± 0.9 vs. 1.2 ± 0.5; p < 0.001) compared with those having cutaneous craniofacial involvement. Conclusions: In light of the potential benefits of employing the multidisciplinary team-based surgical approach demonstrated in this study, such an approach should be adopted to provide comprehensive individualized care to patients with NF-1.

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Restoration of Normal NF1 Function with Antisense Morpholino Treatment of Recurrent Pathogenic Patient-Specific Variant c.1466A>G; p.Y489C

Cited by 3 publications

References 27 publications

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials

The Number of Surgical Interventions and Specialists Involved in the Management of Patients with Neurofibromatosis Type I: A 25-Year Analysis

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