RESUMO
OBJECTIVE: To study the identification of rare genetic variants in the PCDH genetic family in a cohort of transgender women (TGW) and their potential role in gender identity. DESIGN: Exome sequencing and functional ontology analysis. SETTING: Outpatient gender health and reproductive endocrinology clinics. PATIENT(S): A total of 24 TGW and 22 cisgender men (CM). INTERVENTION(S): Exome sequencing followed by variant confirmation through Sanger sequencing and functional classification analysis using the Database for Annotation, Visualization, and Integrated Discovery tool. MAIN OUTCOME MEASURE(S): Identification of rare, functionally significant genetic variants in the PCDH gene family and their prevalence in TGW compared with CM. RESULT(S): Exome sequencing revealed 38,524 genetic variants, of which 2,441 were rare and predicted to be functionally significant. The Database for Annotation, Visualization, and Integrated Discovery analysis demonstrated a statistically enriched functional group, "homophilic cell adhesion via plasma membrane adhesion molecules," containing 55 genes, including 18 PCDH gene family members. A total of 37 rare variants in 21 PCDH genes were identified, with 36 confirmed using Sanger sequencing. A statistically significant increase in these variants was observed in TGW compared with CM (Z = 2.08905). CONCLUSION(S): Transgender women exhibited a greater than threefold increase in functionally significant PCDH gene variants compared with CM. These findings suggest that the PCDH family may play a role in the genetic pathways associated with gender identity in TGW.