Let’s work together to rewrite the narrative.

July 22, 2025

To Whom It May Concern:

We are reaching out because your resource inaccurately represents X-linked inheritance and the impact of X-linked conditions on women and girls.

Females with X-linked conditions, caused by mutations on the X chromosome, can and often do develop symptoms of these diseases. Despite having an extra “unaffected” X chromosome, the severity of these symptoms can be clinically significant and can be as severe as those experienced by males with the same disorders.

Extensive medical research has unequivocally shown that females frequently develop physical symptoms associated with X-linked disorders. Unfortunately, many medical resources have been slow to accurately incorporate this research, leaving the symptoms of women and girls under-acknowledged, under-researched, and under-treated.

To address this, Remember The Girls has launched Rare Rewritten, a campaign to encourage prominent organizations with medical websites to accurately reflect the realities of X-linked conditions. We are requesting that these organizations:

• Describe the inheritance pattern as “X-linked” rather than using the terms “dominant” or “recessive” (the latter distinction many experts suggest is biologically inaccurate);
• Avoid the term “carrier” in descriptions of X-linked inheritance—many females with X-linked conditions are symptomatic and not simply carriers;
• Explain that the likelihood of symptoms in females varies from condition-to-condition and person-to-person due to various factors, one being random versus skewed X-inactivation.

We have provided data and research to support each of these requests and suggest how you can edit your medical website accordingly.

Thank you for your consideration. If you would like additional information, please contact info@rememberthegirls.org. We would also be happy to schedule time for you to discuss this matter with our Medical Advisory Board.

Sincerely,

Meghan Kofod, Chair of Remember The Girls Board of Directors

 

Taylor Kane, Executive Director of Remember The Girls

 

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Introduction to Remember The Girls

Remember The Girls is a 501(c)(3) organization founded in 2017 to support and advocate for women and girls (“carriers”) of rare X-linked conditions. Since its founding more than five years ago, Remember The Girls has expanded into 30+ different countries across the globe. During this time, the organization has supported over 1,400 carriers impacted by 60+ X-linked conditions.

What are X-linked conditions and how are females impacted?

X-linked conditions are caused by mutations, or pathogenic variants, on the X chromosome. They are usually inherited but can also result from spontaneous mutations during embryonic development. Since males typically have one X chromosome, if they have an X-linked pathogenic variant they almost always develop symptoms of the disease. For females (often referred to as “carriers” even though this nomenclature is heavily debated1), who typically have two X chromosomes, it is less clear cut.

Despite having an extra, “unaffected” X chromosome, females who have an X-linked pathogenic variant can, and often do, develop symptoms of the disease. The likelihood and severity of these symptoms is determined by multiple factors, including dosage compensation (the process by which organisms equalize the expression of genes between members of different biological sexes) and skewed X-inactivation (a phenomena that occurs when the X-inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated). However females’ symptoms can be utterly life-changing and as severe as symptoms experienced by males with the same disorders.

For many years, X-linked diseases were thought to almost exclusively affect males. Women and girls with X-linked mutations were believed to be asymptomatic “carriers” of the disease who simply passed the defective X-chromosome on to their offspring. However, over the last few decades, extensive medical research has shown that females frequently do develop physical symptoms associated with X-linked disorders, and in some cases are more severely affected than their male counterparts.

Unfortunately, resources that provide medical information have been slow to catch up and do not accurately reflect reality for females with X-linked conditions. As a result, medical professionals who refer to these sites as well as women themselves may be prevented from understanding the full implications and risks related to their X-linked conditions. Consequently, this leaves females’ symptoms under-acknowledged, under-researched, and under-treated. A 2021 study of X-linked carriers found that “only 10.1% (n = 15/148) of participants felt that they had sufficient access to knowledgeable healthcare providers and/or medical information concerning possible symptoms and/or risks associated with being a carrier.”2

Remember The Girls’ Rare Rewritten campaign

To address this, Remember The Girls has launched the Rare Rewritten campaign to encourage prominent organizations with medical websites to accurately reflect what research has revealed about X-linked conditions. There are three specific aims we ask of these organizations:

1. Describe the inheritance pattern as “X-linked” rather than using the terms “dominant” or “recessive” (the latter distinction many experts suggest is biologically inaccurate);
2. Avoid the term “carrier” in descriptions of X-linked inheritance—many females with X-linked conditions are symptomatic and not simply carriers;
3. Explain that the likelihood of symptoms in females varies from condition-to-condition and person-to-person due to various factors, one being random versus skewed X-inactivation.

Below we provide data and research to back-up each of these three points and suggest alternative ways you can edit your resources accordingly.

X-linked conditions are not dominant or recessive, just X-linked

Descriptions of dominant and recessive inheritance were first used to describe autosomes (chromosomes 1-22, excluding sex chromosomes X and Y), to indicate if a pathogenic variant in one (dominant) or both (recessive) pairs of a chromosome is required to cause a genetic disorder. This description was also applied to sex chromosomes, creating a gap between X-linked conditions considered dominant (thought to affect females) and recessive (not thought to affect females). It’s important to note these categories were established before dosage compensation for X chromosomes was understood, and now have no scientific basis.3

Disorders categorized both as X-linked dominant and recessive can and often do affect females to variable degrees. As stated in a 2004 research article:

“The high proportion of X-linked disorders with intermediate penetrance is difficult to reconcile with standard definitions of X-linked recessive and dominant inheritance. They do not capture the extraordinarily variable expressivity of X-linked disorders or take into account the multiple mechanisms that can result in disease expression in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism. We recommend that use of the terms X-linked recessive and dominant be discontinued, and that all such disorders be simply described as following “X-linked” inheritance.”4

Additional research supports describing these disorders as “X-linked” as opposed to “X-linked dominant” and “X-linked recessive.” A 2008 article highlights the inappropriateness of these categorizations, stating “the terms ‘dominant’ or ‘recessive’ relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X-linked disorders”5 and a 2007 review of 32 X-linked diseases calls for “the terms ‘dominant’ and ‘recessive’ be abandoned and that these disorders be referred to as X-linked.”6 A 2025 article calls for references to X-linked “dominant” and “recessive” inheritance in humans to be dropped and that “these flawed concepts and the definitions associated with them should be removed from biology curricula, textbooks at all levels, and scientific reports, as has already been done in all GeneReviews® entries.”7

The reason this distinction matters is because symptomatic females impacted by disorders categorized as “X-linked recessive” may face greater difficulty in getting their symptoms recognized by medical professionals, as recessive inheritance suggests that two mutations, one inherited by each parent, is necessary for the disease to have an impact. The aforementioned 2025 study states: “Disorders that are traditionally classified as XL “recessive” (many in our intermediate penetrance groups) are often not considered in females, leaving them without a diagnosis despite growing evidence to the contrary.”8

In a research study on women with Fabry disease, the authors note “Fabry disease should no longer be termed an ‘X-linked recessive’ disease and heterozygous Fabry women should not be called carriers, a term that erroneously connotes a lack of symptoms and dangerously delays evaluation and treatment of potentially life-threatening conditions.”9

Women and girls with X-linked conditions aren’t simply “carriers”

Historically, X-linked conditions, such as hemophilia, fragile X syndrome, and Fabry disease were thought to only affect males, with females being usually considered unaffected carriers who simply harbored disease-causing variants that could be passed to their sons. Today, the physical impact these diseases can have on affected females is well-documented in research, and it’s clear that females are not just “carriers.” Unfortunately, the assumption that females with X-linked conditions are asymptomatic carriers still prevails. Despite this, the data speaks for itself:

• Over 80% of women with X-linked adrenoleukodystrophy (ALD) develop spinal cord disease in adulthood.10
• Of the 1077 enrolled females in the Fabry Registry, 69.4% had symptoms and signs of Fabry disease.11
• Women with Alport syndrome are at risk for developing end-stage kidney disease and that the risk of progressive renal failure in females increases with age: about 15–30% reach end-stage kidney disease by age 60.12
• As many as 50% of girls and women who are carriers for hemophilia A or B have factor VIII or IX levels below 50% and are at risk for bleeding symptoms or heavy bleeding related to menstruation or pregnancy. Additionally, abnormal bleeding symptoms may occur with normal factor levels in up to 70% of genetic carriers of hemophilia.13
•  

Clearly, it is a mischaracterization to categorize females with X-linked disorders as carriers, inferring they are asymptomatic. It is entirely possible to avoid the term “carrier” when describing X-linked inheritance. Many X-linked disease communities have completely done away with the term carrier and experts advocate against its use.

For example, a 2021 paper on Hemophilia A and B suggests no longer using the term “carrier” because it “introduces a bias towards female carriers to be asymptomatic.”14 Many X-linked disease-specific patient advocacy groups also support this change in terminology: “At ALD Connect, we refer to female patients as “(a)symptomatic women with ALD” to most accurately represent the manifestation of the disease in women.”15

While it is true that not all females who have an X-linked pathogenic variant will experience symptoms in her lifetime, continuing to push the narrative that women and girls are just carriers may make it difficult for those who are symptomatic to access genetic testing and care for their symptoms. It is also possible for males with X-linked pathogenic variants to remain asymptomatic, but it is not suggested they be referred to as a “carrier” of the disease—this categorization is only placed on females despite the immense data showing many women and girls in this population are not carriers.

It is simple to describe X-linked inheritance and how females may be impacted without using the term “carrier.” Please see this example of an inheritance chart from DiscoverFabry.

https://www.discoverfabry.com/hcp/genetics

 

Females with X-linked conditions may be impacted to varying degrees

When medical resources do describe symptoms experienced by females with X-linked conditions, they often describe these symptoms as “rare” and/or “mild.” While symptoms experienced by females with X-linked conditions are often not as severe as their male counterparts, it is inaccurate and misleading to describe the symptoms of females as rare and/or mild. There are many women who are impacted severely by X-linked conditions and even face risk of death.16

Medical resources must account for the fact that the impact of X-linked conditions on females varies from condition-to-condition and person-to-person. A 2025 study analyzing 57 X-linked conditions found that 43 of them have intermediate or high penetrance in females17 (penetrance refers to the proportion of individuals carrying a particular genetic variant who expresses associated symptoms).

There are numerous phenomena responsible for why some females are more severely impacted than others. One such phenomenon is X-inactivation, the biological process that occurs when the body randomly inactivates one of the X chromosomes in females. Sometimes, by chance, inactivation of the healthy chromosome can happen more often than inactivation of the mutated chromosome, leaving more cells in a female’s body with the disease-causing variant (also known as skewed X-inactivation).18

If medical resources continue to perpetuate the harmful stereotype that our community’s symptoms are rare and/or mild, they feed into the gender bias prevalent within X-linked conditions and medicine as a whole. It’s essential for information on X-linked inheritance and disorders to describe females symptoms as ranging in severity to ensure that girls and women who experience severe symptoms get the recognition, care, and treatment they so desperately need.

 

Conclusion

In conclusion, we hope this letter has provided you with an updated overview of X-linked inheritance and symptom expression in females, and that you are willing to update your website in accordance with these facts. One source accurately representing X-linked conditions is GeneReviews® (see below), and we recommend using their language to update your own resources.

https://www.ncbi.nlm.nih.gov/books/NBK5191/def-item/x-linked/

Again, thank you for your consideration and please respond to this letter or contact info@rememberthegirls.org for more information or to schedule a meeting with our Medical Advisory Board.

 

References

1 Amodio, Federica, Martina Caiazza, Emanuele Monda, Marta Rubino, Laura Capodicasa, Flavia Chiosi, Vincenzo Simonelli, et al. “An Overview of Molecular Mechanisms in Fabry Disease.” Biomolecules 12, no. 10 (October 12, 2022): 1460. https://doi.org/10.3390/biom12101460.

2 Choi, Jennifer, Taylor Kane, Lauren Propst, Sara Spencer, Jamie Kostialik, and Aishwarya Arjunan. “Not Just Carriers: Experiences of X-Linked Female Heterozygotes.” Journal of Assisted Reproduction and Genetics 38, no. 10 (October 1, 2021): 2757–67. https://doi.org/10.1007/s10815-021-02270-6.

3 Basava, Sanjana, Charles J. Billington, Laura Carrel, Leslie G. Biesecker, and William B. Dobyns. “Patterns of X-Linked Inheritance: A New Approach for the Genome Era.” Genetics in Medicine, February 2025, 101384. https://doi.org/10.1016/j.gim.2025.101384.

4 Dobyns, William B., Allison Filauro, Brett N. Tomson, April S. Chan, Allen W. Ho, Nicholas T. Ting, Jan C. Oosterwijk, and Carole Ober. “Inheritance of Most X‐linked Traits Is Not Dominant or Recessive, Just X‐linked.” American Journal of Medical Genetics Part A 129A, no. 2 (August 30, 2004): 136–43. https://doi.org/10.1002/ajmg.a.30123.

5 Zschocke, Johannes. “Dominant versus Recessive: Molecular Mechanisms in Metabolic Disease.” Journal of Inherited Metabolic Disease 31, no. 5 (October 2008): 599–618. https://doi.org/10.1007/s10545-008-1016-5.

6 Dobyns, William B. “The Pattern of Inheritance of X‐linked Traits Is Not Dominant or Recessive, Just X‐linked.” Acta Paediatrica 95, no. S451 (April 2006): 11–15. https://doi.org/10.1111/j.1651-2227.2006.tb02383.x.

7 Basava, Sanjana, Charles J. Billington, Laura Carrel, Leslie G. Biesecker, and William B. Dobyns. “Patterns of X-Linked Inheritance: A New Approach for the Genome Era.” Genetics in Medicine, February 2025, 101384. https://doi.org/10.1016/j.gim.2025.101384

8 Ibid.

9 Wang, Raymond Y., Alicia Lelis, James Mirocha, and William R. Wilcox. “Heterozygous Fabry Women Are Not Just Carriers, but Have a Significant Burden of Disease and Impaired Quality of Life.” Genetics in Medicine 9, no. 1 (January 1, 2007): 34–45. https://doi.org/10.1097/GIM.0b013e31802d8321.

10 Huffnagel, Irene C., Marcel G. W. Dijkgraaf, Georges E. Janssens, Michel van Weeghel, Björn M. van Geel, Bwee Tien Poll-The, Stephan Kemp, and Marc Engelen. “Disease Progression in Women with X-Linked Adrenoleukodystrophy Is Slow.” Orphanet Journal of Rare Diseases 14, no. 1 (February 7, 2019): 30. https://doi.org/10.1186/s13023-019-1008-6.

11 Wilcox, William R., João Paulo Oliveira, Robert J. Hopkin, Alberto Ortiz, Maryam Banikazemi, Ulla Feldt-Rasmussen, Katherine Sims, et al. “Females with Fabry Disease Frequently Have Major Organ Involvement: Lessons from the Fabry Registry.” Molecular Genetics and Metabolism 93, no. 2 (February 2008): 112–28. https://doi.org/10.1016/j.ymgme.2007.09.013.

12 Mastrangelo, Antonio, Marisa Giani, Elena Groppali, Pierangela Castorina, Giulia Soldà, Michela Robusto, Chiara Fallerini, Mirella Bruttini, Alessandra Renieri, and Giovanni Montini. “X-Linked Alport Syndrome in Women: Genotype and Clinical Course in 24 Cases.” Frontiers in Medicine 7 (November 23, 2020). https://doi.org/10.3389/fmed.2020.580376.

13 National Bleeding Disorders Foundation. “MASAC Recommendations for Bleeding Disorders in Women | NBDF,” April 11, 2024. https://www.bleeding.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-286-masac-recommendations-regarding-diagnosis-and-management-of-inherited-bleeding-disorders-in-girls-and-women-with-personal-and-family-history-of-bleeding.

14 Galen, Karin P. M. van, Roseline d’Oiron, Paula James, Rezan Abdul‐Kadir, Peter A. Kouides, Roshni Kulkarni, Johnny N. Mahlangu, et al. “A New Hemophilia Carrier Nomenclature to Define Hemophilia in Women and Girls: Communication from the SSC of the ISTH.” Journal of Thrombosis and Haemostasis 19, no. 8 (August 2021): 1883–87. https://doi.org/10.1111/jth.15397.

15 ALD Connect. “Symptomatic Women.” Accessed April 9, 2025. https://aldconnect.org/what-is-ald/symptomatic-women/.

16 Ohtani, Hayato, Masao Saotome, Atsushi Sakamoto, Kenichiro Suwa, and Yuichiro Maekawa. “Drug-Refractory Heart Failure in Female Carrier of Duchenne Muscular Dystrophy: A Case of X-Linked Dilated Cardiomyopathy.” Internal Medicine (Tokyo, Japan) 62, no. 14 (July 15, 2023): 2089–92. https://doi.org/10.2169/internalmedicine.0745-22.

17 Basava, Sanjana, Charles J. Billington, Laura Carrel, Leslie G. Biesecker, and William B. Dobyns. “Patterns of X-Linked Inheritance: A New Approach for the Genome Era.” Genetics in Medicine, February 2025, 101384. https://doi.org/10.1016/j.gim.2025.101384

18 Shvetsova, Ekaterina, Alina Sofronova, Ramin Monajemi, Kristina Gagalova, Harmen H. M. Draisma, Stefan J. White, Gijs W. E. Santen, et al. “Skewed X-Inactivation Is Common in the General Female Population.” European Journal of Human Genetics 27, no. 3 (March 2019): 455–65. https://doi.org/10.1038/s41431-018-0291-3.