Objective: To study the identification of rare genetic variants in the PCDH genetic family in a cohort of transgender women and their potential role in gender identity.

Design: Exome sequencing and functional ontology analysis.

Setting: Augusta University, including the Equality Clinic of Augusta and the Reproductive Medicine and Infertility Associates Clinic.

Patients: 24 transgender women and 22 cisgender men.

Interventions: Exome sequencing followed by variant confirmation through Sanger sequencing and functional classification analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool.

Main outcome measures: Identification of rare, functionally significant genetic variants in the PCDH gene family and their prevalence in transgender women compared to cisgender men.

Results: Exome sequencing revealed 38,524 genetic variants, of which 2441 were rare and predicted to be functionally significant. DAVID analysis demonstrated a statistically enriched functional group, "homophilic cell adhesion via plasma membrane adhesion molecules" (Benjamini corrected p-value 1.5 x 10-11), containing 55 genes, including 18 PCDH gene family members. A total of 37 rare variants in 21 PCDH genes were identified, with 36 confirmed by Sanger sequencing. A statistically significant increase in these variants was observed in transgender women compared to cisgender men (Z = 2.08905, p= 0.037).

Conclusions: Transgender women exhibited a greater than 3-fold increase in functionally significant PCDH gene variants compared to cisgender men. These findings suggest that the PCDH family may play a role in the genetic pathways associated with gender identity in transgender women.