The review, co-led by Dr. Dan Theodorescu of the University of Arizona Cancer Center and Dr. Dena B. Dubal of the University of California, San Francisco, synthesizes a growing body of evidence from human studies, mouse models, and advanced genomic technologies. The authors argue that the genes located on the sex chromosomes provide specific instructions that shape cellular function throughout an individual’s lifespan. These genetic signals operate both in isolation and in concert with hormonal pathways, creating a dual-layered system of biological regulation. By integrating these disparate findings, the study provides a unified framework for understanding how sex-specific biology influences major disease categories, including cancer, neurological conditions, and cardiometabolic disorders.

In female biology, the mechanism of X-chromosome inactivation is a central theme of the research. Although one of the two X chromosomes is largely silenced early in development to balance gene dosage with males, this process is not absolute. The review highlights that certain genes on the inactive X chromosome remain active, and others can re-activate with age. This phenomenon results in female cells possessing extra doses of specific genetic material compared to male cells. Furthermore, the origin of the active X chromosome appears to be biologically significant. Studies in mouse models indicate that whether the active X is inherited from the mother or the father can influence physiological outcomes. Mice whose cells predominantly relied on the maternal X chromosome exhibited accelerated brain aging and memory decline, suggesting that the parental origin of sex-linked genes has tangible effects on neurodegeneration and cognitive health.

The stability of sex chromosomes also declines with age, a process that has profound implications for disease susceptibility. The review details how cells can lose an entire sex chromosome over time, a phenomenon known as aneuploidy. In women, the loss of an X chromosome is specifically linked to an increased risk of leukemia, although the broader systemic effects of this loss are still being characterized. In men, the loss of the Y chromosome, which is most commonly measured in circulating blood cells, is associated with a wide array of age-related pathologies. These include various cancers, cardiovascular disease, severe infections, and Alzheimer’s disease. The loss of these chromosomes is increasingly being explored not just as a consequence of aging, but as a potential biomarker and even a causal contributor to the development of chronic diseases.

The implications for oncology are particularly striking, as the research provides a mechanistic explanation for sex-based differences in cancer outcomes. Dr. Theodorescu’s laboratory has previously demonstrated that tumors which lose the Y chromosome gain the ability to evade the immune system. This immune evasion provides a biological rationale for why the loss of the Y chromosome has been statistically linked to increased mortality from carcinomas in men. However, the review also notes a paradoxical therapeutic advantage: tumors that have lost the Y chromosome may respond more favorably to immunotherapy. Understanding this complex interplay between chromosomal loss and immune surveillance could allow clinicians to tailor treatment strategies based on the specific genetic profile of a patient’s tumor, moving toward a more personalized approach to cancer care.

Beyond cancer, the review underscores the role of sex chromosomes in cardiovascular and metabolic health. The genetic instructions on the X and Y chromosomes influence how the heart and metabolic systems respond to stress and aging. By identifying these non-hormonal pathways, the study suggests that current diagnostic tools and treatment protocols may be overlooking critical variables. For instance, the differential expression of X-linked genes in heart tissue could explain why men and women present with and respond to heart disease in distinct ways. Integrating sex-chromosome analysis into cardiometabolic research could lead to the development of targeted therapies that address the root genetic causes of these conditions, rather than merely managing their symptoms.

The origins of this comprehensive review can be traced to discussions at the 2025 National Institute on Aging Workshop, which focused on sex differences impacting human health across the lifespan. The collaboration between researchers from the University of Arizona, UC San Francisco, Northwestern University, and other institutions reflects a broader scientific movement toward recognizing sex as a biological variable in all areas of medical research. The authors emphasize that this work is intended to stimulate further investigation and raise awareness of the significant potential of studying sex chromosomes in the context of disease. By highlighting the far-reaching diagnostic and therapeutic implications of this research, the review aims to bridge the gap between basic genetic science and clinical application.

The study also highlights the importance of designing clinical trials that are sex-aware. Historically, many clinical trials have treated men and women as a homogeneous group, often under-representing one sex or failing to analyze outcomes by sex. The review argues that when clinical trials are designed to account for these cellular differences, researchers can translate scientific findings into personalized medical care more effectively. This approach ensures that treatments and diagnostics are tailored to match every patient’s unique genetic profile, rather than relying on population averages that may mask critical sex-specific variations. Such a shift would enhance the precision of medicine and improve outcomes for both male and female patients.

Previous research from Dr. Theodorescu’s group has further illuminated the role of Y-chromosome loss in immune cells. The team found that the loss of the Y chromosome in T cells and cancer cells in men provides tumors with the ability to evade immune detection. This finding offers a concrete explanation for the observed link between Y-chromosome loss and increased mortality from carcinomas. Additionally, recent studies have shown that the loss of the Y chromosome in normal-appearing tissues can serve as an early warning sign of genetic instability. This loss may mark a hidden zone of risk where cancer is likely to develop, providing a potential window for early intervention and prevention. These findings collectively paint a picture of the Y chromosome as a critical regulator of genomic stability and immune function.

Ultimately, this review represents a significant step forward in understanding the biological basis of sex differences in health and disease. By demonstrating that the X and Y chromosomes are active participants in health and disease throughout a person’s life, the study challenges the traditional view of these chromosomes as mere determinants of sex. The research opens new avenues for exploring how sex-specific genetic mechanisms can be leveraged to improve diagnosis, treatment, and prevention of major diseases. As the field of sex-aware medicine continues to grow, the insights provided by this review will likely play a crucial role in shaping future research agendas and clinical practices, ensuring that the unique biology of both men and women is fully accounted for in the pursuit of better health outcomes.

Subject of Research: The role of X and Y chromosomes in determining disease risk, aging, and physiological health independent of hormonal influences.

Article Title: Study: Sex chromosomes drive how bodies deal with cancer, heart health and longevity

Article References: Study: Sex chromosomes drive how bodies deal with cancer, heart health and longevity. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: sex chromosomes, cancer biology, aging, genetics, cardiovascular health, immunology, precision medicine, X-chromosome inactivation, Y-chromosome loss, biomarkers, clinical trials, neurodegeneration

X-linked sideroblastic anemia, or XLSA, arises from pathogenic variants in ALAS2, a gene carried on the X chromosome that provides the blueprint for erythroid-specific 5-aminolevulinate synthase, the first and rate-limiting enzyme in heme biosynthesis. When the enzyme falters, developing red blood cells cannot manufacture heme efficiently, and iron piles up inside their mitochondria instead of being incorporated into hemoglobin. Under the microscope, these iron-laden mitochondria ring the nucleus of immature erythroid cells, producing the ring sideroblasts that give the disease its name. Because the gene sits on the X chromosome, the condition typically follows an X-linked recessive pattern: hemizygous males, who possess only one X chromosome, are usually the ones who fall ill, while heterozygous females often remain asymptomatic or show only mild anemia thanks to their second, healthy copy.

The girl in this report had been flagged during a routine physical examination eight years before referral, when she was initially diagnosed with iron-deficiency anemia. Oral iron supplements failed to lift her hemoglobin, and two years before admission she began complaining of dizziness and fatigue. Testing at that point revealed macrocytic anemia accompanied by folate deficiency, and a bone marrow aspiration showed mild dyserythropoiesis, prompting a diagnosis of nutritional anemia. She was treated with high-dose oral folic acid, later combined with mecobalamin, a form of vitamin B12. The anemia proved stubbornly refractory: hemoglobin hovered around 80 g/L and then slid to roughly 60 g/L after another year of therapy, at which point she was referred for specialist evaluation.

On admission, her hemoglobin measured 59 g/L, with red cell indices pointing firmly toward macrocytosis: a mean corpuscular volume of 113.1 fL, well above the normal range, and a mean corpuscular hemoglobin of 36.9 pg. Reticulocyte analysis told an equally important story. Although the reticulocyte percentage was mildly elevated at 2.48 percent, the calculated reticulocyte production index, adjusted for her severe anemia, came out at approximately 0.40, a value far too low for the degree of anemia. That discrepancy signaled ineffective erythropoiesis: the bone marrow was working hard but producing few usable red cells. White blood cell and platelet counts, crucially, remained normal, arguing against a broad marrow failure syndrome.

Iron studies then delivered a decisive clue. Serum ferritin was markedly elevated at 871.7 micrograms per liter, and serum iron reached 44.12 micromoles per liter, with an unsaturated iron-binding capacity below the detectable limit, together painting a picture of substantial iron overload rather than iron deficiency. Nutritional markers showed borderline folate at 4.14 nanograms per milliliter, interpreted as persistent functional folate deficiency given her continuous supplementation, and a normal vitamin B12 level. Hemolysis markers added further complexity: plasma free hemoglobin was elevated, haptoglobin was nearly abolished, and both indirect and total bilirubin were raised, consistent with hemolytic activity or ineffective erythropoiesis. Erythropoietin, the kidney hormone that drives red cell production, was dramatically elevated at 213.62 mIU/mL, reflecting the marrow’s desperate attempt to compensate. A Coombs test was negative, ruling out autoimmune hemolysis, and the osmotic fragility test was unremarkable.

Morphology told its own story. The peripheral blood smear displayed striking anisocytosis and poikilocytosis, with red cells of wildly varying size and shape, including ovalocytes and teardrop cells. Bone marrow aspiration revealed relative erythroid hyperplasia dominated by intermediate and late erythroblasts, and the biopsy was markedly hypercellular at over 90 percent with erythroid predominance. Flow cytometry found no increase in myeloblasts and no monoclonal lymphoid population, helping exclude a clonal marrow cancer. Globin gene sequencing came back clean, ruling out thalassemia and related hemoglobin disorders, leaving the underlying cause still shrouded.

The breakthrough came from whole exome sequencing of bone marrow mononuclear cells, which uncovered a frameshift insertion in ALAS2: c.1277dupT, resulting in the protein change p.M426Ifs*66. Sanger sequencing confirmed the variant. A frameshift of this kind is catastrophic for protein architecture: the reading frame collapses, and the resulting truncated protein loses critical C-terminal functional domains. Structural modeling with AlphaFold 3 suggested the truncation disrupts the three-dimensional conformation of the enzyme’s active site, specifically displacing the Lys391 residue, the catalytic lysine that forms the essential Schiff base linkage with the pyridoxal 5′-phosphate cofactor. Without that interaction, the enzyme is predicted to be catalytically inert. The variant was therefore classified as highly pathogenic, providing molecular confirmation of XLSA. Notably, the sequencing also surfaced two missense variants in DHX34, predicted deleterious and potentially linked to familial myelodysplastic syndrome or acute myeloid leukemia risk, plus variants in FANCI and BRIP1 classified as uncertain in significance; without segregation or functional data, the team could not assign any of them a causal or modifying role in her blood disorder.

The diagnostic journey required careful exclusion of look-alike conditions. Myelodysplastic neoplasm with SF3B1 mutation, the commonest acquired cause of ring sideroblasts, was considered unlikely given the childhood onset, isolated anemia with preserved white cells and platelets, absence of excess myeloblasts, and the germline ALAS2 finding, though bone marrow iron staining was never performed, so ring sideroblasts could not be formally assessed. Congenital dyserythropoietic anemia, with its characteristic multinucleated erythroblasts and chromatin bridges, found no morphological support, and the features of Pearson syndrome, Diamond-Blackfan anemia, GATA1-related disorders, and telomere biology disorders were all absent. After the molecular diagnosis, the patient continued transfusions as needed for symptomatic anemia, with ferritin monitored but iron chelation not yet started. At last contact she remained transfusion-dependent and subsequently did not return for follow-up, leaving her long-term course unknown.

The case carries broader lessons for hematology. More than 100 pathogenic ALAS2 variants have now been described, scattered across nearly every exon with no clear mutational hotspots, and missense mutations account for roughly 90 percent of cases, making this frameshift a rare and severe class of defect. The authors propose that such profound loss of function may explain the unusually early onset in this female patient. Why she was macrocytic rather than microcytic remains the most intriguing question. Prior work suggests that in symptomatic heterozygous females, skewed X-chromosome inactivation leaves the mutant allele active in erythroid cells, and that circulating red cells derive almost exclusively from wild-type lineages, because ALAS2-deficient clones cannot complete terminal differentiation. Under hypoxic stress and soaring erythropoietin, those surviving wild-type cells may mature prematurely, dividing fewer times and emerging larger, a model the authors frame as hypothetical since X-inactivation studies could not be performed. The family declined further genetic testing, iron staining of stored marrow was never authorized, and transfusion began before pyridoxine response could be tested, though a complete loss-of-function variant was unlikely to respond to the vitamin B6 cofactor anyway. Clinically, the message is clear: when macrocytic anemia resists folate and B12, especially alongside iron overload and a poor reticulocyte response, inherited sideroblastic anemia deserves a place on the differential, and genomic sequencing can end years of diagnostic limbo.

Subject of Research: A novel ALAS2 frameshift mutation causing severe macrocytic X-linked sideroblastic anemia in a female patient

Article Title: Severe Macrocytic Anemia Associated With a Novel ALAS2 Mutation: A Case Report and Literature Review

Article References: Cai, H., Shen, K., Wang, J., Gu, J., Zhang, M., & Xiao, M. (2026). Severe Macrocytic Anemia Associated With a Novel ALAS2 Mutation: A Case Report and Literature Review. Clinical Case Reports, 14(9), Article e73529. https://doi.org/10.1002/ccr3.73529

Image Credits: AI Generated

DOI: 10.1002/ccr3.73529

Keywords: ALAS2, X-linked sideroblastic anemia, macrocytic anemia, heme biosynthesis, ring sideroblasts, whole exome sequencing, iron overload, frameshift mutation, X-chromosome inactivation, ineffective erythropoiesis, refractory anemia, genetic diagnosis

The research, led by Çağrı Doğan of the Department of Medical Genetics at Ordu University Training and Research Hospital together with pediatric neurologist Seren Aydın of Ondokuz Mayıs University Hospital, examined every consecutive individual tested for DMD variants at their centre between January 2022 and February 2026. Forty-seven individuals passed through the diagnostic pipeline, 29 female and 18 male, with a median age of 12.8 years. The team applied two complementary molecular techniques: multiplex ligation-dependent probe amplification, or MLPA, a copy-number detection method available for 45 of the 47 participants, and whole-gene sequencing, performed in 16 individuals and run in parallel with MLPA in 13. All variants were described against the reference transcript NM_004006.3 and classified according to the 2015 ACMG/AMP standards for sequence variants and the 2020 ACMG/ClinGen standards for copy-number variants.

The headline result is deceptively simple: pathogenic variants were identified in 19 of the 47 individuals. Ten of these were probands, the first affected or index individuals in their families to receive a molecular diagnosis, and nine were heterozygous female carriers discovered through cascade screening, the systematic testing of relatives once a familial variant is known. In index testing, the diagnostic yield was 30.3 percent, or ten of 33 individuals tested, with a 95 percent confidence interval of 17.4 to 47.3 percent. Once a familial variant was established, cascade screening detected carriers in nine of 14 relatives tested, a carrier-detection rate of 64.3 percent with a confidence interval of 38.8 to 83.7 percent. Those figures underline a point that geneticists have long emphasised: identifying one patient can protect an entire extended family.

The variant spectrum itself conformed closely to what has been reported across Türkiye and worldwide. Among the nine families with characterised variants, seven carried deletions and two carried single-nucleotide sequence variants: a nonsense change, NM_004006.3:c.701C>G producing p.(Ser234Ter), and a canonical splice-site variant, c.2803+1G>T, which disrupts the invariant guanine at the first position of an intron and is predicted to derail RNA splicing. Strikingly, six of the nine families carried deletions within the so-called distal hotspot spanning exons 45 to 55, a known deletion-prone region of this extraordinarily large gene. Three of the deletions were in-frame, meaning the reading frame of the dystrophin protein was preserved, and four were out-of-frame, consistent with the classical reading-frame rule that links out-of-frame disruptions to the severe Duchenne phenotype and in-frame disruptions to the milder Becker form. Each deletion was cross-verified against public resources, the Leiden Open Variation Database and the DOVE deletion-out-of-frame evaluation tool.

The study also captured a subtler and less frequently discussed facet of dystrophinopathy: female carriers with biochemical evidence of muscle damage. Four heterozygous women, three of whom were probands in their own right rather than relatives of an affected boy, presented with unexplained hyperCKemia, with creatine kinase values ranging from 776 to 2,816 U/L, but no documented muscle weakness. The one carrier who underwent complete evaluation had normal strength and a normal echocardiogram. This pattern reflects the stochastic nature of X-chromosome inactivation, the process by which female cells randomly silence one X chromosome. When inactivation happens to favour the chromosome carrying the mutant DMD allele, enough dystrophin-deficient muscle fibres can exist to leak creatine kinase into the blood, occasionally producing overt disease in women, including cardiomyopathy, decades before anyone suspects a condition classically associated with boys.

Two of the deletions were apparently de novo, arising fresh in the affected child rather than being inherited from a carrier mother, a well-recognised phenomenon in DMD given the enormous size of the gene and its high spontaneous mutation rate. Equally consequential for treatment planning, none of the probands in this series carried a variant amenable to an approved exon-skipping oligonucleotide. These antisense drugs, including eteplirsen, golodirsen, viltolarsen and casimersen, work by masking specific exons during RNA splicing so that the reading frame is restored and a shorter but partly functional dystrophin protein can be made. Eligibility depends entirely on the exact exon boundaries of the deletion or point mutation, which is why a precise molecular diagnosis is not merely academic but the gateway to genotype-matched therapy.

Technically, the study illustrates the standard two-step architecture of DMD molecular diagnostics. MLPA, first described by Schouten and colleagues in 2002, uses pairs of probes that ligate only when bound to their target sequences and are then amplified, allowing relative quantification of all 79 exons of the DMD gene in a single reaction; it remains the most efficient way to detect the exon deletions and duplications that account for the majority of pathogenic DMD variants. When MLPA is negative, sequencing of the gene captures the point mutations, small insertions and deletions, and splice-site changes that copy-number assays cannot see. Running both methods in parallel, as this centre did in 13 cases, accelerates turnaround. The authors’ adherence to Human Genome Variation Society nomenclature and to consensus ACMG classification frameworks ensures that their variants can be compared directly with entries in international databases such as the TREAT-NMD global mutation registry, which has catalogued more than 7,000 DMD mutations.

The regional significance of the work lies in establishing a baseline. Previous Turkish series, including a 2019 analysis of 260 dystrophinopathy patients and later single-centre surveys, had sketched the national mutation spectrum, but the Central-Eastern Black Sea provinces had remained a blank spot on that map. The new data suggest that the local spectrum is broadly congruent with national and global patterns, dominated by deletions concentrated in the distal hotspot. That congruence matters for genetic counselling: it means clinicians in the region can reasonably apply the established genotype-phenotype correlations and exon-skipping eligibility frameworks without needing region-specific correction, while still sequencing each family’s variant to confirm its exact boundaries.

The authors are careful about the limits of what such a small series can prove. With only ten probands, the reported proportions are descriptive rather than prevalence estimates, and genotype-based phenotype assignment in individual patients requires prospective confirmation with longitudinal follow-up. The retrospective, single-centre design also means the cohort reflects referral patterns and test availability at one hospital rather than systematic population screening. Still, the cascade-screening outcome, nine additional heterozygotes identified from fourteen relatives, is a concrete demonstration of why molecular diagnosis should trigger immediate family testing. Every carrier identified can be offered cardiac surveillance, reproductive counselling including prenatal and preimplantation genetic options, and the knowledge that ultimately saves the next generation of boys in the family from a delayed diagnosis.

For a disease in which early corticosteroid treatment, standardised cardiac and respiratory care, and emerging gene-targeted therapies all depend on catching patients early, the message from Türkiye’s Black Sea coast is clear: find the variant in one child, and the laboratory work has only just begun. The first regional map of DMD variants is now drawn, and its most important lines may be the family trees radiating outward from each proband.

Subject of Research: Mutational spectrum of DMD gene variants and cascade screening for Duchenne and Becker muscular dystrophy in Türkiye

Article Title: Mutational Spectrum of DMD Gene Variants and Cascade Screening Outcomes in the Central-Eastern Black Sea Region of Türkiye: A Single-Centre Retrospective Study

Article References: Doğan, Ç., & Aydın, S. (2026). Mutational Spectrum of DMD Gene Variants and Cascade Screening Outcomes in the Central-Eastern Black Sea Region of Türkiye: A Single-Centre Retrospective Study. Molecular Biology Reports, 53(1), Article 1600. https://doi.org/10.1007/s11033-026-12785-9

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12785-9

Keywords: Duchenne muscular dystrophy, DMD gene, Becker muscular dystrophy, cascade screening, MLPA, female carriers, exon deletions, genetic testing, dystrophinopathy, hyperCKemia, Türkiye, X-chromosome inactivation

X chromosome inactivation begins early in embryonic development in female mammals, when each cell generally shuts down one of its two X chromosomes. The choice is usually random, producing a mosaic of cells in which either the maternal or paternal X chromosome remains active. Once established, the inactive chromosome is maintained through cell division by a combination of DNA methylation, histone modifications and changes in three-dimensional chromatin organization. This creates a stable but highly regulated state in which most genes on the inactive chromosome are inaccessible to the cell’s transcriptional machinery.

A central coordinator of this process is XIST, a long non-coding RNA produced from the X chromosome destined for inactivation. Rather than encoding a protein, XIST spreads across the chromosome from which it is transcribed and recruits molecular complexes that remodel chromatin. These complexes include proteins involved in histone deacetylation, Polycomb-mediated repression and DNA methylation. Together, they convert the chromosome into a compact structure known as heterochromatin. Although XIST is essential for silencing most X-linked genes, some genes escape inactivation, an important feature that contributes to biological differences between individuals.

The consequences of X chromosome inactivation become particularly visible when a woman carries a mutation in an X-linked gene. If the chromosome carrying the mutation is preferentially silenced, cells may continue to use the healthy copy, limiting disease manifestations. If the normal chromosome is silenced instead, a larger proportion of cells may express the mutant allele. This uneven pattern, known as skewed X chromosome inactivation, can arise through chance during development or through selective survival of cells carrying one active chromosome. It helps explain why people with the same genetic mutation can experience substantially different symptoms.

Rett syndrome provides one of the clearest examples. The disorder is usually caused by mutations in MECP2, a gene that encodes a protein involved in interpreting DNA methylation and regulating neuronal gene expression. In female carriers, the proportion of neurons expressing mutant or healthy MECP2 can strongly influence neurological function. Preferential inactivation of the chromosome with the faulty MECP2 gene may reduce symptoms, while inactivation of the chromosome carrying the normal gene can intensify them. Experimental studies in animal models have further suggested that restoring healthy MECP2 activity after disease features have appeared may reverse some neurological and behavioral abnormalities.

The review also describes evidence connecting X chromosome inactivation with disease severity in Fabry disease, Becker muscular dystrophy, hemophilia, X-linked Alport syndrome and chronic granulomatous disease. However, the relationship is not always straightforward. X chromosome patterns can differ between tissues, and a blood sample may not accurately represent what occurs in the brain, heart, kidneys or skeletal muscle. Age, tissue-specific selection and the expansion of particular cell populations can also alter the balance over time. These complications make it difficult to use a single X chromosome inactivation measurement as a universal predictor of clinical outcome.

Improved measurement technologies are therefore becoming essential. The HUMARA assay, which analyzes methylation near a polymorphic region of the androgen receptor gene, has long been used as a convenient indirect estimate of X chromosome activity. Bisulfite sequencing can provide more detailed information about methylated DNA, while RNA-based methods can reveal which alleles are actively transcribed. More recently, long-read nanopore sequencing combined with CRISPR-Cas9 enrichment has offered a way to examine selected genomic regions while simultaneously assessing DNA methylation. Such methods could eventually help clinicians identify patients whose healthy alleles remain available for therapeutic reactivation.

The most ambitious strategy is to awaken selected genes on the inactive X chromosome without globally disrupting the chromosome’s silencing system. This distinction is critical because broad X chromosome reactivation could produce excessive gene expression and potentially harmful cellular effects. Researchers are investigating targeted approaches involving antisense molecules, genome-editing systems, epigenetic drugs and manipulation of XIST-associated pathways. In cellular and animal models of Rett syndrome, reactivation of the silent healthy MECP2 allele has demonstrated the principle that an inactive gene may remain therapeutically recoverable long after embryonic development.

The review highlights ACVR1 and PDPK1 among the signaling and regulatory factors being studied as possible intervention points. In experimental systems, inhibiting these pathways has influenced XIST expression, chromatin structure and the accessibility of genes on the inactive chromosome. Some studies have reported partial restoration of gene activity and improvements in disease-related cellular abnormalities. Translating these findings into human therapies will require precise delivery, tissue-specific control and careful monitoring of unintended gene activation. Even so, X chromosome biology is moving from a fundamental topic in developmental genetics toward a possible platform for personalized treatment, in which a patient’s inactivation pattern could determine whether a silenced healthy gene can be safely brought back online.

Subject of Research: X chromosome inactivation, skewed X chromosome inactivation and therapeutic reactivation of genes on the inactive X chromosome in X-linked genetic disorders.

Article Title: From inactivation to intervention: X chromosome silencing in disease pathogenesis and emerging therapeutic strategies

Web References: https://doi.org/10.1016/j.gendis.2025.101964; https://www.sciencedirect.com/journal/genes-and-diseases

References: Yuan Fu, Xuling Tan, Lixia Qin, Chunyu Wang, “From inactivation to intervention: X chromosome silencing in disease pathogenesis and emerging therapeutic strategies,” Genes & Diseases, Volume 13, Issue 5, 2026, Article 101964.

Image Credits: Genes & Diseases

Keywords: X chromosome inactivation, XCI, skewed XCI, XIST, Rett syndrome, MECP2, Fabry disease, hemophilia, muscular dystrophy, gene reactivation, epigenetics, CRISPR-Cas9, nanopore sequencing, X-linked disorders