Clinical, Genetic and Molecular Divergences Between Full Mutation and Premutation in Fragile X Syndrome: A Systematic Review

IF 1.6 4区医学 Q3 DEVELOPMENTAL BIOLOGY

International Journal of Developmental Neuroscience Pub Date : 2025-09-23 DOI:10.1002/jdn.70054

Hajar Souski, Yousra Benmakhlouf, Mohcine Bennani Mechita

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Abstract

Background

Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability (ID) and the primary monogenic cause of autism spectrum disorder (ASD) worldwide. The disorder arises from a CGG trinucleotide expansion of more than 200 repeats, known as a full mutation (FM) that occurs in the fragile X messenger ribonucleoprotein 1 (FMR1) gene locus at Xq27.3. This expansion induces hypermethylation of the gene's promoter region, leading to epigenetic silencing and a consequent reduction in the expression of the FMR1 (FMRP)—a protein critical for synaptic plasticity and maturation. While the genetic basis of FXS is well established, further clarification is needed to understand how variations in the FMR1 gene lead to divergent clinical outcomes. This systematic review explores the differences in clinical features, genetic variations and molecular mechanisms between individuals with a FM, clinically diagnosed with FXS and premutation (PM) carriers with fragile X premutation–associated conditions (FXPAC), with a focus on implications for improving support for individuals with ID and their families.

Methods

Three databases (PubMed, Web of Science and Scopus) were systematically searched, guided by a variety of keywords, to identify qualitative, empirical research about clinical, genetic and molecular differences between FM and PM carriers. A total of 62 articles were examined, and 44 were included in the review.

Results

The information is presented in the following categories: clinical features, genetic variations, molecular mechanisms, diagnostics and treatments. Three primary themes are discussed: (1) variability in clinical manifestations, (2) genetic insights and diagnostic advancements and (3) current and emerging management strategies. Research gaps are also highlighted along with perspectives and implications for further research.

Conclusion

The identification and treatment of FXS and FXPAC remains a major public health and clinical concern. This systematic literature review provides a more robust understanding of FXS and the clinical, genetic and molecular distinctions between FM and PM carriers. Despite growing knowledge of the condition, significant efforts are still required to refine diagnostic tools, develop targeted interventions and support individuals and families affected by FXS.

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脆性X综合征中完全突变和预突变的临床、遗传和分子差异：系统综述。

背景：脆性X染色体综合征（Fragile X syndrome， FXS）是世界上最常见的智力残疾（ID）遗传形式，也是自闭症谱系障碍（ASD）的主要单基因病因。这种疾病是由CGG三核苷酸扩增超过200个重复引起的，称为全突变（FM），发生在脆弱的X信使核糖核蛋白1 （FMR1）基因位点Xq27.3。这种扩展诱导了基因启动子区域的超甲基化，导致表观遗传沉默，并随之减少FMR1 （FMRP）的表达，FMRP是突触可塑性和成熟的关键蛋白。虽然FXS的遗传基础已经建立，但需要进一步澄清，以了解FMR1基因的变异如何导致不同的临床结果。本系统综述探讨了FM患者、临床诊断为FXS和携带脆性X预突变相关疾病（FXPAC）的PM携带者在临床特征、遗传变异和分子机制方面的差异，重点探讨了对ID患者及其家庭的支持。方法：系统检索PubMed、Web of Science和Scopus三个数据库，以多种关键词为导向，对FM和PM携带者的临床、遗传和分子差异进行定性、实证研究。共审查了62篇文章，其中44篇被纳入综述。结果：从临床特征、遗传变异、分子机制、诊断和治疗等方面介绍了相关信息。讨论了三个主要主题：(1)临床表现的可变性；(2)遗传见解和诊断进展；(3)当前和新兴的管理策略。研究差距也突出，以及对进一步研究的观点和影响。结论：FXS和FXPAC的鉴别和治疗仍然是一个重大的公共卫生和临床问题。这篇系统的文献综述为FXS以及FM和PM携带者之间的临床、遗传和分子差异提供了更有力的理解。尽管对这种疾病的了解越来越多，但仍需要付出巨大的努力来完善诊断工具，制定有针对性的干预措施，并为受FXS影响的个人和家庭提供支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Developmental Neuroscience 医学-发育生物学

CiteScore

3.30

自引率

5.60%

发文量

审稿时长

6-12 weeks

期刊介绍： International Journal of Developmental Neuroscience publishes original research articles and critical review papers on all fundamental and clinical aspects of nervous system development, renewal and regeneration, as well as on the effects of genetic and environmental perturbations of brain development and homeostasis leading to neurodevelopmental disorders and neurological conditions. Studies describing the involvement of stem cells in nervous system maintenance and disease (including brain tumours), stem cell-based approaches for the investigation of neurodegenerative diseases, roles of neuroinflammation in development and disease, and neuroevolution are also encouraged. Investigations using molecular, cellular, physiological, genetic and epigenetic approaches in model systems ranging from simple invertebrates to human iPSC-based 2D and 3D models are encouraged, as are studies using experimental models that provide behavioural or evolutionary insights. The journal also publishes Special Issues dealing with topics at the cutting edge of research edited by Guest Editors appointed by the Editor in Chief. A major aim of the journal is to facilitate the transfer of fundamental studies of nervous system development, maintenance, and disease to clinical applications. The journal thus intends to disseminate valuable information for both biologists and physicians. International Journal of Developmental Neuroscience is owned and supported by The International Society for Developmental Neuroscience (ISDN), an organization of scientists interested in advancing developmental neuroscience research in the broadest sense.