Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Importance The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls. Design, Setting, and Participants This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023. Exposure Genomic identification of an additional X or Y chromosome Main Outcomes and Measures Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio. Results Of 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean SD, 4.30 2.72 vs controls: mean SD, 3.90 2.47; 47,XYY: mean SD, 4.45 2.90 vs controls: mean SD, 3.82 2.50) and health care utilization (eg, median IQR outpatient encounters per year: 47,XXY, 22.6 11.8-37.8 vs controls, 16.8 9.4-28; 47,XYY: 21.4 12.4-33.8 vs controls: 17.0 9.4-28.2), while several measures of HRQOL were lower (eg, mean SD self-reported physical function: 47,XXY: 34.2 12 vs control mean SD 37.8 12.8; 47,XYY: 36.3 11.6 vs control 37.9 12.8). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median IQR encounters per year: 26.6 14.9-43.2 vs 22.2 11.3-36.0) but lower Charlson Comorbidity Index scores (mean SD: 3.7 2.7 vs 4.5 4.1). Conclusion and Relevance In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.