Prevalence, Morbidity, and Mortality of 1,609 Men with Diagnosed and Undiagnosed Sex Chromosome Aneuploidy: Results from the Diverse Million Veteran Program (MVP) Cohort

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe 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 <15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. ObjectivesDetermine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); describe military service metrics of men with SCAs; compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis to matched controls. DesignCross-sectional, case-control SettingUnited States Veterans Administration Healthcare System ParticipantsBiologic males enrolled in the MVP biobank with genomic identification of an additional X or Y chromosome (cases); controls matched 1:5 on sex, age, and genetic ancestry Main Outcome(s) and Measure(s)Prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index (CCI); rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; standardized mortality ratio (SMR) ResultsAn additional X or Y chromosome was present in 145 and 125 per 100,000 males in the MVP, respectively, with the highest prevalence among men with European and East Asian ancestry. At a mean age of 61{+/-}12 years, 74% of male veterans with 47,XXY and >99% with 47,XYY remained undiagnosed. Individuals with 47,XXY (n=862) and 47,XYY (n=747) had similar military service history, all-cause SMR, and age of death compared to matched controls. CCI and healthcare utilization were higher among individuals with SCA, while several measures of HRQoL were lower. Men with a clinical diagnosis of 47,XXY had higher healthcare utilization but lower comorbidity score compared to those undiagnosed. Conclusion and RelevanceOne in 370 males in the MVP cohort have SCA, a prevalence comparable to estimates in the general population. While these men have successfully served in the military, they have higher morbidity and report 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. KEY POINTSO_LIComparable to the general population, approximately 1 in 370 male veterans have a sex chromosome aneuploidy, but most are undiagnosed. C_LIO_LIMen with X or Y chromosome aneuploidy successfully complete US miliary duty with similar service history compared to their 46,XY peers. C_LIO_LIMedical comorbidities and healthcare utilization metrics are higher in male veterans with 47,XXY and 47,XYY during aging, however life expectancy is similar to matched controls. C_LI