X-Linked Disorders: Epigenetic and Environmental Modulation of Phenotypes
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".
Deadline for manuscript submissions: 30 September 2025 | Viewed by 305
Special Issue Editors
Interests: gene-environment interaction; X-linked disorders; epigenetics; epidemiology
Special Issue Information
Dear Colleagues,
The X-chromosome likely contains 800 to 875 identified protein-coding genes and approximately 250–750 non-coding RNAs, depending on the source and annotation method used. Most of these genes are involved in the regulation and development of bone, neural, blood, hepatic, renal, retinal, ear, cardiac, and skin tissue, as well as teeth. Over 533 known genetic disorders are associated with X-chromosome genes. The more common well-characterized X-linked disorders include color vision deficiency (CVD), hemophilia A and B, Duchenne muscular dystrophy (DMD), agammaglobulinemia, G6PD deficiency (favism), Fabry disease, Alport syndrome, and ichthyosis. While some X-linked disorders cause a significant health burden and even death, others lead to functional impairments that, though less severe, may still impact quality of life.
Traditionally, X-linked disorders have been studied through the lens of classical Mendelian inheritance, with a strong emphasis on sex-based expression, with males being more frequently and severely affected due to their hemizygous status, compared to females, who have a mosaic of X-linked gene expression. However, increasing evidence points to a more nuanced reality related to X-chromosome content and dosage regulation: female individuals may also exhibit disease manifestations, particularly in cases of skewed X-chromosome inactivation or silencing, homozygosity, chromosomal translocations, or haploinsufficiency.
Moreover, emerging research suggests that environmental exposures and stochastic epigenetic factors can influence the expression and severity of X-linked conditions, such as Fabry disease, Rett syndrome, and Kabuki syndrome. Stochastic processes including meiotic segregation, mitochondrial partitioning, X-inactivation, and the dynamic DNA binding of transcription factor assemblies all exhibit randomness and DNA mutations that may involve environmental fluctuation (radiation or the presence of pollutants) or random genetic repair system malfunctions. In addition, recent findings indicate differences in the prevalence of CVD among individuals of similar genetic backgrounds born in different environments, suggesting a possible role played by non-genetic modulators.
Therapeutic approaches to mitigating X-linked disorders include classical and emerging strategies, such as medications and symptomatic treatments, dietary interventions, enzyme/hormone replacement therapy, stem cell transplantation, cell-based therapies, gene editing and gene replacement therapies, and RNA-targeted therapies.
As Guest Editors, we are pleased to invite contributions to this Special Issue, which will explore X-linked disorders from an integrative perspective, encompassing not only genetic content and mechanisms but also the possible role of environmental influences and epigenetic regulation in shaping the manifestation of congenital and acquired X-linked disorders in a sex-specific manner. We welcome original research articles, reviews, and case studies that explore the following topics:
- Genetic mechanisms and novel mutations in X-linked disorders;
- The role of X-inactivation and its clinical implications;
- Environmental and epigenetic modifiers of gene expression;
- Sex-specific disease expression;
- Epidemiological studies across diverse populations;
- Implications of variability in gene expression among individuals, tissues, cell types, and stages of life.
This Special Issue will advance our understanding of X-linked conditions and foster a broader dialog that will bridge basic science—in terms of genetics, epigenetics, and environmental cues – and clinical manifestations and therapeutic avenues.
We look forward to receiving your valuable contributions.
Dr. Yoram Chaiter
Dr. Yossy Machluf
Guest Editors
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Keywords
- X-linked disorders
- epigenetics
- environmental factors
- gene expression
- clinical manifestations
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