Genetics and the Women’s Olympics 

Genetics and the Women’s Olympics  

By John Schloss, Ph.D. 

When I first heard about the controversy surrounding the 2024 women’s Olympic boxing contender, Algeria’s Imane Khelif, involving her Y chromosome, I assumed her karyotype was an example of Klinefelter’s syndrome.  During 1968 women’s Olympics, Barr body detection was introduced as a verification method for female gender.  Someone with an XXY karyotype would meet the 1968 criteria for female gender.  Any individual with two X chromosomes has a dark spot, easily determined under a light microscope, in the nucleus of each cell.  This dark, heterochromatic spot is one of the two X chromosomes that are randomly inactivated in each cell with the 47,XXY genetic makeup.  Barr bodies are a convenient marker for females (46, XX) or individuals with Klinefelter’s syndrome (47,XXY).   

However, in 1991, Barr body analysis was replaced with PCR (polymerase chain reaction)-based detection of the SRY locus on the Y chromosome.  Use of PCR-dependent detection of the Y chromosome would have distinguished someone with a normal female karyotype (46,XX) from someone with a classical Klinefelter’s karyotype (47,XXY).  These tests became irrelevant in 1999, when it was decided to abandon compulsory gender verification in the women’s Olympic competition.  Imane Khelif was disqualified from the 2023 world boxing championship, due to the presence of her Y chromosome.  Individuals with Klinefelter’s syndrome typically present as males at birth.¹  It is the most common disorder of sex chromosomes, affecting one of every 660 births.¹  Since the XXY karyotype can easily go undetected, it has been estimated that the true frequency could be as high as 0.6% of all ‘males’.  George Washington, the first president of the United States, is suspected of having Klinefelter’s syndrome.²

Imane Khelif qualified for the women’s Olympics because she was born anatomically female.  Does this mean she is not genetically 47,XXY?  There are examples of individuals with the XXY karyotype and a female phenotype.^3-5 In one example, the individual had the normal determinants of male sexuality on the Y chromosome (SRY and ZFY) and normal SRY-box-related genes on autosomal chromosomes (e.g., SOX9 on chromosome 17).⁵ This phenotypically normal female was not a mosaic, where some cells have the normal female karyotype (e.g., 46,XX/47,XXY or 46,XX/47,XXY/48,XXYY).⁵ So, it is possible for an individual to be anatomically female at birth; possess a 47,XXY karyotype; have Barr bodies in the nuclei of all cells; and have the SRY locus on the Y chromosome, meeting all criteria for participation in the 1991-1999 women’s Olympics, despite possessing a Klinefelter’s karyotype. Based on her birth certificate, Imane Khelif was born female.   

Imane Khelif could be born female, even if she had the typical male karyotype, 46XY.  The only difference would be the absence of a Barr body in each cell’s nucleus. There are three recognized disorders that can result in an anatomical female with an XY karyotype:  (1) complete gonadal dysgenesis also known as SWYER syndrome; (2) Congenital Adrenal Hyperplasia (CAH) from deficit of the 17-α hydroxylase/17–20 lyase enzyme; and (3) Congenital Androgenic Insensitivity Syndrome (CAIS).⁶ The frequency of these disorders is quite low ranging from one per 10-16 thousand births for CAH,⁷ to one per 20-60 thousand births for CAIS,⁵ to one per 80 thousand births for SWYER.⁶  

Summary:  Based on information available in the popular press, it is not possible to tell whether the karyotype of Imane Khelif includes 47,XXY, 46,XY, or some other combination of X and Y chromosomes.  A cursory review of the peer-reviewed scientific literature suggests that it does not matter which combination of X and Y chromosomes an individual inherits, since they can still present as an anatomically correct female at birth and develop as such, unaware of their Y chromosome.  One difference between 47,XXY and 46,XY females will be the absence of Barr bodies in the nucleus of cells derived from the latter.  To present as an anatomically correct male at birth and develop as such, requires the SRY gene on the Y chromosome and other genetic elements, some of which are on somatic chromosomes and not present on either the X or Y chromosome.  Migration of the SRY gene to other chromosomes (e.g., by X/Y terminal exchange during meiosis) will also allow for birth of a karyotypical female (46,XX) that presents as an anatomically correct male (Chapelle Syndrome first described in 1964).⁸ It is not possible from someone’s anatomy to determine their makeup with respect to X and Y chromosomes.   

1. Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A (2013) 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet 163C(1):55-63. https://doi.org/10.1002/ajmg.c.31349  
2. Amory JK (2004) George Washington’s infertility: why was the father of our country never a father? Fertil Steril 81(3):495-9. https://doi.org/10.1016/j.fertnstert.2003.08.035  
3. Saavedra-Castillo E, Cortés-Gutiérrez EI, Dávila-Rodríguez MI, Reyes-Martínez ME, Oliveros-Rodríguez A (2005) 47,XXY female with testicular feminization and positive SRY: a case report. J Reprod Med 50(2):138-40. 
4. Khandelwal A, Agarwal A, Jiloha RC (2010) A 47,XXY female with gender identity disorder. Arch Sex Behav 39(5):1021-3. https://doi.org/10.1007/s10508-010-9628-x 
5. Thangaraj K, Gupta NJ, Chakravarty B, Singh L (1998) A 47,XXY female. Lancet 352(9134):1121. https://doi.org/10.1016/S0140-6736(05)79762-2  
6. Meyer KF, Freitas Filho LG, Silva KI, Trauzcinsky PA, Reuter C, Souzab MBM (2019) The XY female and SWYER syndrome. Urol Case Rep 26:100939. https://doi.org/10.1016/j.eucr.2019.100939  
7. Uslar T, Olmos R, Martínez-Aguayo A, Baudrand R (2023) Clinical Update on Congenital Adrenal Hyperplasia: Recommendations from a Multidisciplinary Adrenal Program. J Clin Med 12(9):3128. https://doi.org/10.3390/jcm12093128  
8. Adrião M, Ferreira S, Santos Silva RS, Garcia M, Dória S, Costa C, Castro-Correia C, Fontoura M (2020) 46,XX male disorder of sexual development. Clin Pediatr Endocrinol 29(1): 43–45. https://doi.org/10.1297/cpe.29.43