Detection and Impact of Mosaic Loss of Chromosome X

Sex-chromosome mutations are among the most detrimental to human health. Most are lethal or result in major loss of function, and their germline location allows mutations to affect multiple generations. A mosaic mutation causes an individual to have multiple populations of cells with different genotypes [1]. There are two types of mosaic chromosomal mutations (mCAs) that occur in germline cells. One has links to the Y chromosome in men (mLOY) while the other has links to the X chromosome in women (mLOX) [2]. Each mutation occurs in a de novo fashion, meaning it is not inherited from parental gametes, and results in unequal chromosomal cell fractions [1]. Mosaic loss of chromosome X, also known as mLOX, creates a mixture of cells with the expected two X chromosomes and cells with only one X chromosome [3]. Current research is unable to explain why mLOX develops and how to treat, prevent, and identify those afflicted by the disorder. Its effects on human health are a major concern, as the mutation has been linked to cancers, immune disorders, and other bodily dysfunctions. In this review, I will introduce mosaic loss of the X chromosome, the populations it affects, the health risks associated with the mutation, and a summary of current detection strategies and technologies. 

Background 

In females, one of the two X chromosomes in each cell is randomly inactivated to ensure correct gene expression and conserve energy in the cell [1, 2]. In a fully functioning cell, the inactive X chromosome will transform into a Barr body to help equalize gene expression between males and females so that only one X chromosome is expressed per cell [4]. The inactive X chromosome (Xi) is one of the last chromosomes to replicate during meiosis, making it more vulnerable to replication errors. Machiela (2016) used Illumina Human-Methylation 450k microarray data to demonstrate that mLOX typically resulted in the loss of the inactive X chromosome. This method of research involves measuring DNA methylation patterns, which allows researchers to look at epigenetic modifications to DNA, focusing on chromosomal modifications rather than changes to DNA sequences. Rare instances of gains of the inactive X chromosome or replacement of the active chromosome with the inactive one were also recorded [1]. The study hypothesized that DNA damage to Xi could result in the chromosome remaining unreplicated and unable to be passed down to daughter cells. Once the inactive X chromosome is lost, the new daughter cells cannot regenerate the missing information. This results in a waterfall effect, where all cells originating from the mutated cell are affected, creating mosaic regions in the body where groups of cells are missing one or more X chromosomes. Areas afflicted with mLOX continue to grow and have increased effects as the affected individual ages. When detected, mLOX typically involves around 2% of the cells in the body, and those with mLOX have 1,000 times higher mutation rates than those with somatic mCAs [2, 3]. Although it affects only a small percentage of cells in the body, accumulating mosaic cells with missing X chromosomes can have vast health implications.

Risk Factors of Development 

mLOX is typically developed post-zygotically and was originally thought to remain contained within the individual it develops, as a "missing" chromosome cannot be inherited. However, certain genetic components have been identified as increasing susceptibility to mLOX formation. Liu (2024) and Zekavat (2021) identified genetic markers that predispose individuals to mLOX development. They posit that while the missing chromosome itself cannot be inherited, there is a hereditary component that increases the risk of developing [3, 5]. In other words, the chance of X chromosome mosaicism is inherited, not the trait itself. Liu (2024) identified 56 genetic variants that increase mLOX susceptibility, including a rare variant in the FBXO10 gene that correlates with a twofold increased risk of development [3]. Biomarker levels, gene variants, and associated health concerns can be used to identify mLOX in potential patients and serve as a starting point for understanding the underlying mechanisms behind mLOX development. Current detection technologies cannot predict and identify mosaic events without genome analysis, which can be costly and time-consuming. 

Certain lifestyle factors have been linked to mosaicism development, and correlational studies have identified biomarkers that are associated with mLOX. These factors can all be used to identify mLOX, as current detection technologies remain rudimentary. Using the MoChA pipeline and array genotyping, which detects chromosomal and genetic sequence abnormalities. Young (2024) identified major risk factors for mLOX development. Smoking, alcohol consumption, decreased physical activity, and high BMI were all significantly associated with increased mosaic events [6]. Increased physical activity, reduced stress levels, and moderate alcohol consumption were all found to lessen the chances of mLOX creation and development. These results are inconclusive, and more research is needed to better support whether these factors are causational or simply correlational.

mLOX disproportionately affects women, as it preferentially affects the inactivated X chromosomes only present in females. Women are four times more likely to have a mutation causing incidents of mosaicism compared to men, and approximately 5-8 % of women from the UK will develop mLOX within their lifetime [2, 7]. It can be estimated that this rate is similar to other populations of women, though more studies are needed to draw a firmer conclusion. Within the female population, the risk of developing mLOX increases with age. Liu (2024) performed a genome-wide analysis on 883,574 female participants from worldwide biobanks. The study identified genetic precursors and lifestyle factors that indicate a higher risk of mLOX development. They estimated that 3.0% of participants under 40 years of age developed the mutation, which jumped to 35.0% of participants after 80 years of age [3]. Other studies also found an increased risk of development after the age of 45 [1, 5]. These trends suggest that mLOX develops during a woman's late forties and accumulates over time, spreading slowly throughout the body as aging occurs and affecting cellular regions. Zeliha Gözde Turan, researcher at the University of Liverpool, explained that because reproduction happens early in the human lifespan, the effects of natural selection weaken with age. This allows late-acting, slightly deleterious mutations to accumulate and contribute to age-related health decline [8]. Essentially, once the body passes reproductive age, evolution no longer filters out as many harmful mutations, since they will not be passed to the next generation. In the example of mLOX, weaker evolution effects mean that the mutation accumulates in women over 40, disproportionately affecting a mainly non-reproducing population.

Effects of mLOX

In addition to lifestyle factors, many molecular markers were identified as possible effects of the mosaic mutation. Hubbard (2023) investigated 32 serum biomarkers in 436,784 cancer-free participants and found that individuals with mLOX have increased lipid biomarkers. High cholesterol, lower IGF-1 levels, higher protein levels, and increased enzymes associated with liver disease and bile duct dysfunction were all linked to patients with mLOX [7]. Variants found in the Liu study, including the FBXO10 gene listed above, were found in genes associated with DNA damage repair and lymphoid processes. Impacted lymphoid variants could explain the connection between mLOX and immune system complications mentioned later in the Zekavat and Liu studies. Variants in DNA damage repair correlate with Machiela's hypothesis that DNA damage renders the Xi chromosome unable to be replicated. It is important to note that these factors are not the specific causes of mLOX or the direct effects of its development. More research is needed to understand the direct effects of the mutation, but current research remains correlational. 

Mosaicism in the X chromosome is also associated with various blood cancers and immune disorders. Liu (2024) found significant associations between mLOX development and overall leukemia, chronic lymphoid leukemia, and acute myeloid leukemia [3]. Zekavat (2021) performed another genome-wide association study on 768,762 individuals from the United Kingdom. The study found that individuals with a high cell fraction of missing X chromosomes had higher hematologic cancer risk as well as higher chances of developing chronic lymphocytic leukemia, polycythemia vera, and myeloid leukemia [5]. The X chromosome contains genes critical for blood production and blood clotting, also known as hemophilia. Impacted X chromosome function, such as in the case of mLOX, can deregulate these processes, which could explain the increased risk of blood cancers seen in this study. X chromosome mosaicism has also been found to increase the risk of immune complications, including sepsis, COVID-19 hospitalizations, and respiratory, digestive, and genitourinary system infections [3, 5, 7]. Sonehara (2025) also found that mLOX may indirectly cause immune dysregulation and impact the immune response, though they concluded reflected the larger genomic stability that results from aging rather than a major health driver [9].

Newer studies have also begun linking mental and physical stress as an indirect effect of mosaicism. Young (2024) found mental stress to be statistically significantly linked to mLOX development, to which extreme levels have been correlated with suicidal behavior [6]. Otsuka (2024) analyzed postmortem blood samples from suicide deaths and their descendants and found that suicide descendants had significantly increased levels of mLOX [10]. Mental stress and suicide risk may themselves be correlated, and more research is needed to determine if mLOX development is a direct cause of suicide or depression. One posited connection is that undiagnosed mLOX mutations cause health problems such as the ones listed above, and if left untreated, can cause increased mental stress. However, more investigation into stress, mutation, and self-harm is needed for a more well-rounded conclusion to be found.

Conclusion 

Mosaicism affecting the X chromosome has severe health concerns, yet the mechanisms behind its creation and widespread effects remain largely unstudied. Long-term, widespread studies focusing on the underlying process of mLOX development are required to better understand the exact function of the mutation and how it specifically affects certain cells. Detection technologies remain rudimentary, and though correlational studies have been conducted, no clear mechanism has been discovered to produce mLOX. More longitudinal studies are required to understand the frequency of mLOX in the population and its heritable, long-term effects. Identifying whether there are any hereditary components can help educate medical practitioners as to whether mLOX can be passed through generations, and the risk factors involved in having children. Though genome-wide sequencing and analysis are possible, it remains a time-consuming and expensive process, making it difficult for every possible individual patient to undergo genome analysis. Understanding how mLOX develops is crucial to the treatment and prevention of the mutation, as loss of the inactive X chromosome has the potential to affect almost every part of the genome and human development. The discovery of this information will help researchers develop mitigation and identification strategies for cancers and diseases associated with the mutation to help those afflicted with mosaicism. 

About the Author: Grace Hill

Grace Hill is a fourth-year Genetics and Genomics major at UC Davis, graduating in the Spring of 2026. Interested in the intersection of clinical practice and genomic engineering, she hopes to pursue a career in medicine focusing on improving public genetic literacy and applying emerging technologies. In her free time, she plays on the Women’s Club Water Polo team, mentors with the BioLaunch Mentor Collective, reads, and spends time with friends.

Author’s Note

While writing my Winter 2025 UWP102 literature review assignment, I chose to focus on a type of mutation I had briefly learned about in my genetics coursework that had intrigued me. After researching more, I became enraptured by the topic and wanted to teach readers about this mutation, its detection technologies, and why it is concerning and relevant today. With future hopes of genetic counseling, it was particularly important to me to educate on the prevalence and vast health impacts of the phenomenon.

References

1. Machiela, Mitchell J., Wei Zhou, Elizabeth M. Karlins, et al. 2016. “Female Chromosome X Mosaicism Is Age-Related and Preferentially Affects the Inactivated X Chromosome.” Nature Communications 7: 11843. https://doi.org/10.1038/ncomms11843
2. Watson, Christopher J., and John R. Blundell. 2023. “Mutation Rates and Fitness Consequences of Mosaic Chromosomal Alterations in Blood.” Nature Genetics 55: 1677–1685. https://doi.org/10.1038/s41588-023-01490-z
3. Liu, A., G. Genovese, Y. Zhao, M. Pirinen, S. M. Zekavat, K. A. Kentistou, Z. Yang, K. Yu, C. Vlasschaert, X. Liu, et al. 2024. “Genetic Drivers and Cellular Selection of Female Mosaic X Chromosome Loss.” Nature 631 (8019): 134–141. https://doi.org/10.1038/s41586-024-07533-7
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