A Comprehensive Analysis of Variations in Sex Characteristics Across OMIM

Document Type

Journal Article

Publication Date

12-29-2025

Journal

American journal of medical genetics. Part A

DOI

10.1002/ajmga.70040

Keywords

DSD; VSC; VSC/DSD; differences of sex development; human phenotype ontology; intersex; variations in sex characteristics

Abstract

Variations in Sex Characteristics (VSC), also referred to as intersex traits or Differences of Sex Development (DSD), encompass diverse chromosomal, gonadal, and anatomical sex traits. The full spectrum of VSC remains under-recognized, partly due to diagnostic approaches that prioritize classic VSC/DSD conditions. We developed a 103-term Focused Genitourinary VSC Glossary (FGV Glossary) using Human Phenotype Ontology (HPO) terms and screened 8359 Online Mendelian Inheritance in Man (OMIM) entries for inclusion. Associated genes were evaluated for coverage in clinical DSD panels and assessed in ClinVar for pathogenic variants linked to VSC/DSD phenotypes. We identified 539 OMIM entries (~6.4%) with at least one FGV Glossary term. These entries were enriched for genitourinary, breast, and endocrine phenotypes. Of 56 high-confidence VSC/DSD genes identified, 23 (41%) were absent from a current representative DSD gene panel. A curated ClinVar review showed that 3 of these 23 genes (DHX37, SPRY4, TBX3) had pathogenic variants clearly associated with VSC/DSD traits. Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield and guide comprehensive, multidisciplinary clinical care.

Department

Pediatrics

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