The eXtraordinarY Babies Study: Natural History of Health and Neurodevelopment in Infants with Sex Chromosome Trisomy

摘要 背景：性染色体三体(SCT)包括Klinefelter(XXY)、XYY综合征和X三体(XXX)，1/1发生 每500个新生儿中。在儿童时期，语言和学习障碍、多动症、自闭症和情绪化的风险增加 精神错乱。在医学上，SCT与XXY的睾丸衰竭、XXX的卵巢衰竭有关，并且都有增加的发病率。 以及因胰岛素抵抗、癫痫发作和其他健康状况的高风险而死亡。产前SCT诊断有DRAS- 在过去的十年里，随着无创性产前筛查(NIPS)的广泛应用，这一比例在美国急剧增加。EXtraordi- Nary Baby研究于2017年启动，并招募了规模最大、最多样化的产前诊断SCT队列 日期，包括271名婴儿，前瞻性地从2个月到3-4岁进行跟踪调查，并进行详细的医疗、激素和 发育表型与包括超过1250个生物菌群的纵向生物库相结合。结果表明， SCT中以前没有描述的医学特征，发育里程碑的详细获取，以及确定的不同- 早期的言语和行为特征被认为是后来诊断为自闭症、阅读障碍和多动症的“危险信号”。 家长们分享了经验，强调了改进遗传咨询模式的必要性。 参与者对学龄期的跟踪是至关重要的，因为阅读障碍等重要的共病， ADHD、自闭症和内分泌功能障碍正在出现，表型变异性扩大，发育和健康 结果变得更能预测以后的功能。在这个更新项目中，我们的目标是：(1)描述和比较 通过对前SCT的前瞻性研究，了解SCT的神经发育、医学问题和激素谱的自然历史。 超乎寻常的婴儿进入早期学龄，(2)识别SCT中发育和健康状况不良的结果， 特别注意可改变的发展、健康和环境因素，以指导未来的干预试验；以及(3) 开发一种循证的、父母知情的产前遗传咨询的最佳实践模式，以满足 SCT人群。 方法：当前研究参与者(n=262；XXY=174，XYY=25，XXX=54，XXYY/XXXY=9)和60名新招募的儿童将 完成7-8岁以下的年度评估。新的招聘将针对那些来自代表不足的种族和 民族，社会经济地位低，农村地区，以及XYY和XXX。人口统计、健康和家族史，以及 将收集教育/干预措施，以及以下评估：(1)认知、心理和运动功能；(2) 身体和性腺测量和(3)生活质量。统计模型将对比每个SCT组的纵向轮廓 并与人口标准进行比较。线性模型和Logistic回归将被用来检验潜力和风险之间的关联。 TIAL早期危险因素和7岁时选定的结果。生物样本将被添加到生物储存库。家长体验- 产前SCT诊断的序列将通过混合方法进行分析，以开发基于证据的遗传学 咨询资源。影响：对最大的产前确诊为SCT的儿童进行的纵向研究提供了 新的资源，将提供SCTS发育和医学概况的自然历史信息，指导遗传咨询， 确定干预试验的目标，为新生儿筛查提供信息，并提供无价的数据和生物检验库 为将来的研究做准备。

ABSTRACT 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 dras- tically increased over the past decade in the US with more widespread noninvasive prenatal screening (NIPS). The eXtraordi- narY 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 1250 biospecimens. Results have identified medical features not previously described in SCT, detailed acquisition of developmental milestones, and identified differ- ences in early speech and behavior profiles known to be ‘red flags’ of later diagnoses such as autism, dyslexia, and ADHD. Parents shared experiences highlighting the need for improved genetic counseling models. Follow-up of participants into the school-age years is critical as important comorbidities such as reading disabilities, ADHD, autism and endocrine dysfunction being to emerge, phenotypic variability broadens, and developmental and health outcomes become more predictive of later functioning. In this renewal project we aim to: (1) Describe and compare the natural history of neurodevelopment, medical problems and hormonal profiles of SCT through prospective study of the eX- traordinarY Babies cohort into early school age, (2) To identify of poor developmental and health outcomes in SCT, with special attention to modifiable factors of development, health and environment to guide future intervention trials, and (3) To develop an evidence-based, parent-informed best practice model for prenatal genetic counseling unique to the needs of the SCT population. Approach: Current study participants (n=262; XXY=174, XYY=25, XXX=54, XXYY/XXXY=9) and 60 newly recruited children will complete annual assessments up to 7-8 years of age. New recruitment will target those from underrepresented racial and ethnic groups, low socioeconomic status, rural locations, and XYY and XXX. Demographics, health and family history, and education/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 be used to test the association between poten- tial early risk factors and selected outcomes at age 7. Biological samples will be added to the biorepository. Parent experi- ences with the prenatal SCT diagnosis will be analyzed via a mixed method approach to develop evidence-based genetic counseling resources. Impact: Longitudinal study of 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.