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<p>Neurofibromatosis Type 1 (NF1), an autosomal dominant genetic disorder, is characterized by extensive clinical variability, posing significant challenges for prognosis and patient management. Despite being caused by mutations in a single gene, <i>NF1</i>, the expressivity of the disease ranges from mild cutaneous manifestations to severe, life-threatening complications, including malignant tumors, skeletal deformities, and cognitive impairments. This paper provides a comprehensive review of the genetic determinants underlying this phenotypic heterogeneity. We begin by elucidating the molecular genetics of NF1, detailing the structure and function of the <i>NF1</i> gene and its protein product, neurofibromin, and the diverse spectrum of mutations that cause the disorder. Neurofibromin’s critical role as a negative regulator of the Ras signaling pathway is central to understanding the pathophysiology of NF1. Subsequently, the paper explores the primary mechanisms driving phenotypic variation, including established genotype-phenotype correlations, the influence of genetic modifiers, the impact of somatic mosaicism and second-hit mutations, and the emerging role of epigenetic and environmental factors. By synthesizing current knowledge, this review aims to construct a holistic view of the complex interplay between the primary <i>NF1</i> mutation and the broader genetic landscape that ultimately shapes the clinical presentation of NF1. Understanding these determinants is crucial for advancing diagnostic capabilities, developing personalized therapeutic strategies, and improving clinical outcomes for individuals affected by this complex disorder.</p>

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Genetic and non-genetic factors influencing phenotypic variability in neurofibromatosis type 1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Patricia Bianca Clissa,
  • Sabri Saeed Sanabani

摘要

Neurofibromatosis Type 1 (NF1), an autosomal dominant genetic disorder, is characterized by extensive clinical variability, posing significant challenges for prognosis and patient management. Despite being caused by mutations in a single gene, NF1, the expressivity of the disease ranges from mild cutaneous manifestations to severe, life-threatening complications, including malignant tumors, skeletal deformities, and cognitive impairments. This paper provides a comprehensive review of the genetic determinants underlying this phenotypic heterogeneity. We begin by elucidating the molecular genetics of NF1, detailing the structure and function of the NF1 gene and its protein product, neurofibromin, and the diverse spectrum of mutations that cause the disorder. Neurofibromin’s critical role as a negative regulator of the Ras signaling pathway is central to understanding the pathophysiology of NF1. Subsequently, the paper explores the primary mechanisms driving phenotypic variation, including established genotype-phenotype correlations, the influence of genetic modifiers, the impact of somatic mosaicism and second-hit mutations, and the emerging role of epigenetic and environmental factors. By synthesizing current knowledge, this review aims to construct a holistic view of the complex interplay between the primary NF1 mutation and the broader genetic landscape that ultimately shapes the clinical presentation of NF1. Understanding these determinants is crucial for advancing diagnostic capabilities, developing personalized therapeutic strategies, and improving clinical outcomes for individuals affected by this complex disorder.