The “Sex-check” and Genetic Determinism in Genetic Testing

The “Sex-check” and Genetic Determinism in Genetic Testing

Genetic testing offers an opportunity for individuals to learn more about their risk of developing certain diseases and their genealogy.  Both direct to consumer (genetic tests you can order online, such as 23andMe or Ancestry.com) and clinical genetic testing are becoming much more accessible and popular as genetic testing technology advances. As of 2019, more than 2.6 million people had purchased direct to consumer genetic tests in the United States (Regaldo 2019). As genetic technology advances, our understanding of the ethical, legal, and social implications of genetic technology has not kept pace (Phillips et al. 2018; Schaper and Schicktanz 2018), particularly in regard to one process of quality control – the “sex check”.

The sex check is common practice in clinical genetics, direct-to-consumer genetic testing, and genetic research (Mathias et al. 2016; Coleman et al. 2016; Hunter-Zinck et al. 2020; Turner et al. 2011). It involves comparing an individual’s sex chromosomes against their sex or gender. Sometimes, the only information that is available in a clinical or research setting may be either their sex or gender, and it may not be clear which is reported. Although sex and gender are often used interchangeably in genetic research and by genetic scientists, they capture different constructs.

Sex refers to an individual’s sexual chromosome composition or their biological sex characteristics while gender refers to an individual’s internal sense of their gender, whether it be male, female, both, or neither (TSER n.d.). Running the sex check during quality control in genetic testing checks that individuals with a sex or gender that may not be self-reported but is listed as Female have XX chromosomes and individuals with sex or gender that may not be self-reported but is listed as Male have XY chromosomes.

The purpose of this check is to make sure that the sample being processed belongs to the correct individual. Individuals whose sex chromosomes do not match their reported sex or gender are followed up with to ensure the correct sample is being processed for the right person (in the case of clinical or DTC genetic testing) or are removed from a dataset (in a research setting). The utility of this measure is limited; as pointed out by Warmerdam et al. (2021), it does nothing to differentiate sample mix ups between two individuals with the same sex chromosomes. It is only applicable to sample of individuals which contains multiple sexes, and for a sample which contains half people with XX chromosomes and half people with XY chromosomes, it is only 50% effective (Warmerdam et al. 2021). Standard, primary sample quality control procedures in genetic testing include identifying individuals with poor DNA quality, with high variation across autosomal chromosomes, mismatched sex information, removing duplicated or related samples, and running analysis stratified by continental ancestry (Mills, Barban, and Tropf 2020). Additionally, clinical genetic testing, and typically research, involves signing an informed consent at the time that the sample for genetic testing is collected.

Ample procedures are already in place to ensure that the correct sample is matched to the right person. The argument to include the sex-check in genetic testing is weak at best and at its worst it has the effect of either singling transgender individuals or excluding transgender people from genetic research altogether.

Excluding transgender people from genetic research or singling them out in clinical practice directly contributes to the stigma and discrimination that transgender folks experience within the American healthcare system (Institute of Medicine (US) Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities 2011). Multiple studies have found that transgender individuals do not seek out healthcare services due to previous negative experiences and medical distrust, resulting in decreased healthcare access and worse health outcomes within the transgender community (Barnes, Morris, and Austin 2020; Kosenko et al. 2013; Rolle et al. 2021).

The sex check inherently “others” transgender individuals not only by reminding them of something they may already feel insecure about , but also by perpetuating the idea that biological sex determines gender, a concept tied to genetic determinism (McKeague and Terry 2019). Genetic determinism refers to the belief that our genetic makeup is the sole factor in determining our individual characteristics (Sarraf and Woodley of Menie, Michael A. 2019). This concept has historically been weaponized against the transgender community, particularly in public policy.

An example of the implications of genetic determinism for transgender people and how this ideology results in exclusion of trans individuals lies in the growing national conversation on transgender athletes and whether they should be allowed to participate in competitive sports. Controversial “sex verification,” including molecular tests to identify sex chromosomes, were introduced to determine eligibility for athletes to compete in gendered sporting events in the 1960s (Tucker and Collins 2010). Today, transgender athletes are permitted to compete in the category that is consistent with their gender identity given that they follow certain protocols, such as hormone level monitoring. However, there is still debate as to whether a performance advantage exists for trans women, leading some to argue for reintroduction of genetic testing in this arena. Lia Thomas is the most recent trans athlete to be under public scrutiny for competing in women’s sports (Ghorayshi 2022). This is a reiteration of the same genetic determinism that trans athletes and trans people more broadly have faced for years. Cisgender people see trans people as a threat in sports because of their perceived, unfair advantage due to their biological makeup.

Efforts are being made to move away from genetic determinism (particularly in the clinical space) to be more inclusive of transgender patients, but they often do not go far enough to protect trans people who are receiving clinical care. For example, genetic counselors are currently adapting their practices to be more welcoming and inclusive of folks with varying gender identities. Some of these efforts include use of intake forms that ask for pronouns and gender identity, creation of new pedigree nomenclature that affirms trans and non-binary individuals’ gender identities, and implementation of gender-inclusive language when describing genetics concepts (Barnes, Morris, and Austin 2020; Rolle et al. 2021; Sheehan et al. 2020). Still, an abundance of research describes the negative experiences of trans patients undergoing genetic counseling or genetic testing in a clinical setting. Experiences in a healthcare setting induce anticipatory anxiety for trans people, and it is the responsibility of clinicians to create safety and clarity (Barnes, Morris, and Austin 2020; Rolle et al. 2021).

Clinicians need to clearly communicate with trans patients how and when information about their sex and gender will be used in genetic testing (Barnes, Morris, and Austin 2020). Additionally, it is necessary to take additional steps that validate individuals’ gender identities and to use inclusive language throughout the process of genetic counseling and genetic testing (Barnes, Morris, and Austin 2020; Rolle et al. 2021).

Genetic testing companies are taking steps to be more inclusive by creating “best practices” for processing genetic tests for their transgender clients. For example, Color Genomics has integrated questions about gender identity and sex assigned at birth into their health history intake, as well as a disclaimer that gendered information within a genetic test report may not reflect their identity (Mar et al. 2020). Direct-to-consumer genetic testing company 23andMe allows for customers to self-report their “profile sex” with which they identify, and advise that during sample processing if “genetic sex” does not match selected profile sex they will notify the customer, who can validate that the difference was expected (23andMe n.d.). Other genetic testing companies also notify or call patients when this occurs to ask them to confirm their sex assigned at birth. This process of validating the difference between profile sex and chromosomal sex, in practice, singles out trans people by creating an incredibly uncomfortable experience and presenting an additional barrier to care.

Another concern in the process of genetic testing lies in the return of results. Genetic testing reports that make suggestions for preventative care are inherently gendered. For example, a positive result for a BRCA1 mutation may state that women with a mutation should receive regular mammograms without considering that not all individuals with breasts may identify as women. For both 23andMe and Color Genomics, the test report that is returned to consumers still contains gendered information, such as labels like “maternal” or “paternal”, no matter how the customer or their relatives identify.  Altogether, the consequence of the practices of these genetic testing companies are only somewhat successful in preventing negative experiences or interactions with their transgender clients.

To make genetic testing more approachable and more inclusive to individuals whose gender identities don’t match their sex chromosomes, we need to carefully consider how the sex check is being used and exactly how necessary it is. Given all of this information, we make the following recommendations:

First, we call for genetic testing companies and genetic researchers to think carefully about the necessity of the sex-check, and to implement alternative quality control procedures when appropriate. While alternative methods compare other phenotypic characteristics with a sample’s genotype, new methods which rely on the generation of polygenic risk scores have been shown to be more effective in identifying sample mix ups (Warmerdam et al. 2021).

When necessary, researchers and genetic testing companies should utilize and collect information on both sex assigned at birth and gender identity to ensure that individuals whose chromosomes do not match their reported sex are not singled out in the genetic testing process.

Additionally, we suggest updating language in the genetic testing process to be more inclusive, such as changes to pedigree nomenclature and avoidance of gendered language such as “maternal” or “paternal”. Moving forward, it is our responsibility as genetics professionals to address the historical exclusion and discrimination of trans people within the fields of clinical and research genetics and to ensure that an individual’s genetic makeup will not be weaponized against them.

References

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