Intersex/Differences of Sex Development (I/DSD) Traits: Exploring Their Association with 15% of Phenotypically Detailed Genetic Disorders

Abstract

AbstractThe study of Intersex traits or Differences of Sex Development (I/DSD) is an imperative area within medical genetics that confronts a long-standing problem: the prevalence of these conditions in the population is not fully clear, likely undercounted, and therefore no universally agreed upon numbers exist. Proportions among rare differences are not fully understood. While each specific I/DSD condition is individually rare, together they are estimated to affect about 0.7-1.7% of people worldwide (Fausto-Sterling, 1993). Over 10% of individuals with I/DSD traits exhibit comorbidities affecting other bodily systems, suggesting a broader, systemic impact of these conditions. The comprehensive phenotypic spectrum and systemic implications of I/DSD traits are not well-documented, likely due to social, cultural, and privacy concerns that may contribute to the under-phenotyping of genital variations. This research aims to delineate the disease landscape associated with I/DSD traits. By using the Online Mendelian Inherit ance in Man (OMIM) database, a comprehensive resource for human genes and genetic disorders, we compiled an expert list of 155 Human Phenotype Ontology (HPO) terms that encompass the entirety of the medically defined I/DSD space. These terms were cross-referenced with the OMIM database to pinpoint diseases annotated with these HPO terms. Out of 8,181 phenotypically detailed diseases listed in OMIM and included in the HPO database, we discovered that 1,264 (15.5%) have associations with I/DSD-related HPO terms, signifying their presence in I/DSD traits. This substantial overlap underscores the need to rethink I/DSD not just as isolated anomalies but as a continuum of conditions that are crucial for a broader understanding of health issues. It also highlights that I/DSD traits are relatively common within the realm of rare differences, emphasizing the necessity for specialists, such as clinical geneticists, to be well-versed in I/DSD. Our findings call for a shift in the medical community’s perception and approach to studying I/DSD traits. Further research is required to confirm these associations and to explore the relationship between I/DSD traits and overall health.