The Use of Whole Exome Sequencing in a Cohort of Transgender Individuals to Identify Rare Genetic Variants

Abstract

Approximately 0.5–1.4% of natal males and 0.2–0.3% of natal females meet DSM-5 criteria for gender dysphoria, with many of these individuals self-describing as transgender men or women. Despite recent improvements both in social acceptance of transgender individuals as well as access to gender affirming therapy, progress in both areas has been hampered by poor understanding of the etiology of gender dysphoria. Prior studies have suggested a genetic contribution to gender dysphoria, but previously proposed candidate genes have not yet been verified in follow-up investigation. In this study, we expand on the topic of gender identity genomics by identifying rare variants in genes associated with sexually dimorphic brain development and exploring how they could contribute to gender dysphoria. To accomplish this, we performed whole exome sequencing on the genomic DNA of 13 transgender males and 17 transgender females. Whole exome sequencing revealed 120,582 genetic variants. After filtering, 441 variants in 421 genes remained for further consideration, including 21 nonsense, 28 frameshift, 13 splice-region, and 225 missense variants. Of these, 21 variants in 19 genes were found to have associations with previously described estrogen receptor activated pathways of sexually dimorphic brain development. These variants were confirmed by Sanger Sequencing. Our findings suggest a new avenue for investigation of genes involved in estrogen signaling pathways related to sexually dimorphic brain development and their relationship to gender dysphoria.

Sex vs Gender: A Biological Location for Gender, not Sex.

“…Nevertheless, because of the temporal nature of this linking and the consecutive organization of body and brain, the two processes can be influenced independently. In a tiny percentage of people, 0.5-1.4% of natal males and 0.2-0.3% of natal females (Theisen et al, 2019), this alignment is unconventional.…”

Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones

“…Alternatively, it may be hypothesized that biological factors that act during intrauterine or early development and are involved in the development of gender dysphoria, are also related to bone development programming. For example, a whole-exome sequencing study in transgender individuals found 21 variants in 19 genes associated with estrogen activated pathways of sexually dimorphic brain development ( 20 ). These variants in estrogen receptor–activated pathways might also play a role in bone mineral acquisition.…”

Ciudadanía sexual y discordancia de género: revisión teórica y reflexiones problemáticas.

“…Los aportes teóricos de la hoy se denomina discordancia de género se pueden categorizar en tres grupos. Los estudios médico-esencialistas (Fine, 2011;De Vicente, Berdullas y Castilla, 2012;García Falgueras et al, 2005;Segovia y Guillamón, 1993;Zubiaurre-Elorza et al, 2013;Carrillo et al, 2010;Bao y Swaab, 2011;Fernández y Pásaro, 2017;Junger, et al 2014;Smith, Junger, Derntl y Habel, 2015;Theisen, et al 2019) que afirman que las características biológicas (genético-anatomofisiológicas) de las personas son inalterables y anteriores a la cultura, así como la hipótesis del determinismo genético, hormonal y cerebral de la identidad sexo-genérica y su inmutabilidad.…”