Identification of rare genetic variants in the PCDH genetic family in a cohort of transgender women

Abstract

ObjectiveTo 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. DesignExome sequencing and functional ontology analysis. SettingAugusta University, including the Equality Clinic of Augusta and the Reproductive Medicine and Infertility Associates Clinic. Patients24 transgender women and 22 cisgender men. InterventionsExome 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 MeasuresIdentification of rare, functionally significant genetic variants in the PCDH gene family and their prevalence in transgender women compared to cisgender men. ResultsExome 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). ConclusionsTransgender 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.