PROJECT SUMMARY Background: Sex Chromosome Trisomies (SCT) including Klinefelter (XXY), XYY syndrome, and Trisomy X (XXX), occur in 1 out of every 500 births. In childhood there are increased risks for language and learning disabilities, ADHD, autism, and emotional disorders. Medically, SCTs are associated with testicular failure in XXY, ovarian failure in XXX, and all have increased morbidity and mortality due to high risks for insulin resistance, seizures, and other health conditions. Prenatal SCT diagnosis has drastically increased over the past decade in the US with more widespread noninvasive prenatal screening (NIPS). The eXtraordinarY Babies Study was launched in 2017, and has enrolled the largest and most diverse prenatally diagnosed SCT cohort to date, including 271 infants followed prospectively from 2 months to 3-4 years of age with detailed medical, hormonal, and developmental phenotyping coupled with a longitudinal biobank including over 1300 biospecimens. Results have identified medical features not previously described in SCT, detailed acquisition of developmental milestones, and identified differences in early speech and behavior profiles known to be `red flags' of later diagnoses such as autism, dyslexia, and ADHD. Despite successes described above, we have gaps in our dataset due to COVID research restrictions during a significant portion of our data collection period, and uncertainty about renewal funding for the continuation of this project. The focus of this administrative supplement year will be to complete comprehensive data collection for the 36-month in-person visits (including direct neurodevelopmental assessment and biospecimen collection that was not possible due to COVID). This will allow for achievement of a complete dataset through 36-months of age which was the primary endpoint for the 1st phase of the study (2017-2022). We aim to: (1) Describe and compare the natural history of neurodevelopment, medical and hormonal profiles of SCT, and (2) To identify predictors of phenotypic variability in developmental and health outcomes in SCT. We will maintain the current Biobank. Approach: Current study participants (n=271) ranging from 12 to 60 months of age will complete an annual assessment, with goals of completing 50 36-month in-person visits, and the remainder conducted by telehealth. Demographics, health, family history, and interventions will be collected, along with assessments of: (1) cognitive, psychological and motor functioning; (2) physical and gonadal measures and (3) quality of life. Statistical models will contrast longitudinal profiles for each SCT group and compare to population norms. Linear models and logistic regression will test the association between potential early risk factors and selected outcomes at 36 months. The biorepository will be expanded and maintained. Impact: The largest cohort of prenatally identified children with SCT provides a novel resource that will inform the natural history of ...