Demographic Composition of Participants in Sex Chromosome Aneuploidy Studies across the Globe: a 20-year Systematic Review.

Background: Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations.

Methods: We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE^® ALL, Embase, and Web of Science. Studies were included if they enrolled ≥10 participants and excluded if they were case reports, reviews, or meta-analyses. We extracted data from 1,474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For U.S.-based studies reporting race/ethnicity, we compared pooled participant demographics to national census data.

Results: SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the U.S. (23.6%). Reporting rates of race or ethnicity for U.S. papers increased over the 20-year observation period, with an average increase of 1.5% ± 0.4% per year (p = 0.003), peaking in 2024 with 61.4% of U.S.-based papers presenting demographics. When reported, studies consistently overrepresented non-Hispanic White (p<0.001) and college-educated (p<0.001) participants relative to U.S. census benchmarks.

Conclusions: This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the U.S., where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.