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

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.