The eXtraordinarY Babies Study: Natural History of Health and Neurodevelopmentin Infants and Young Children with Sex Chromosome Trisomy

项目总结 背景：性染色体三体(SCT)包括Klinefelter(XXY)、XYY综合征和X三体 (Xxx)，每500个新生儿中就有一个发生。在儿童时期，语言和学习的风险会增加 残疾、多动症、自闭症和情绪障碍。在医学上，SCT与XXY的睾丸衰竭有关， XXX中的卵巢衰竭，由于胰岛素抵抗的高风险，所有人的发病率和死亡率都有所增加， 癫痫发作和其他健康状况。在过去的十年中，产前SCT诊断大幅增加 美国有更广泛的无创性产前筛查(NIPS)。非同寻常婴儿的研究是 于2017年启动，并已招募了迄今为止规模最大、最多样化的产前诊断SCT队列，包括 271名婴儿前瞻性地从2个月到3-4岁进行了详细的医疗、激素和 发育表型与包括1300多种生物在内的纵向生物库相结合。结果是 确定了SCT中以前没有描述的医学特征，获得了详细的发育里程碑，以及 识别早期言语和行为特征的差异，这些差异被认为是后来诊断的“危险信号”，例如 自闭症、阅读障碍和多动症。 尽管取得了上述成功，但由于COVID研究的限制，我们的数据集中仍存在差距 我们数据收集期间的很大一部分时间，以及关于延续这一阶段的续签资金的不确定性 项目。今年行政补充年的重点将是完成全面的数据收集工作 36个月的面对面访问(包括直接神经发育评估和生物样品收集，即 由于COVID，这是不可能的)。这将允许在36个月内实现完整的数据集， 是该研究第一阶段(2017-2022年)的主要终点。我们的目标是：(1)描述和比较 神经发育的自然历史，SCT的医学和激素特征，以及(2)确定SCT的预测因素 SCT患者发育和健康结局的表型变异性。我们将维持目前的生物库。 方法：目前的研究参与者(n=271)年龄从12个月到60个月不等，将完成每年一次的 评估，目标是完成50次为期36个月的面对面访问，其余由远程保健进行。 将收集人口统计学、健康、家族史和干预措施，以及以下评估：(1)认知、 心理和运动功能；(2)身体和性腺测量；(3)生活质量。统计模型 将对比每个SCT组的纵向轮廓，并与人群正常值进行比较。线性模型与Logistic 回归将检验潜在的早期风险因素与36个月后选定结果之间的关联。这个 生物储存库将得到扩建和维护。影响：最大的产前确诊的儿童患有 SCT提供了一种新的资源，它将为SCTS中的发展和医学概况的自然历史提供信息， 指导遗传咨询，确定干预试验的目标，通知新生儿筛查，并提供 为未来的研究提供无价的数据和生物质谱库。

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 developmental and medical profiles in SCTs, guide genetic counseling, identify targets for intervention trials, inform newborn screening, and provide an invaluable data and biospecimen repository for future research.