Gene, Brain and Behavior in Turner Syndrome

描述（由申请人提供）：特纳综合征（TS）是一种非常常见的遗传疾病，其特征是表型女性缺乏X染色体物质。TS的物理表型特征很明显，身材矮小和性腺发育不良是最常见的。认知上，TS患者通常表现出正常的整体智力功能，在语言领域具有优势；然而，许多人在视觉空间和执行功能以及社会心理技能方面表现出明显的缺陷，特别是在面部和情绪处理方面。这种TS认知行为表型的神经相关性最近开始被探索，包括大脑结构和功能的神经影像学研究。然而，从这些研究中获得有意义的见解的能力受到样本量小、参与者年龄范围大以及外源性激素治疗状态异质性的限制。此外，遗传效应（如X染色体印迹）对TS神经功能和认知行为结果的影响尚未得到充分研究。因此，本项目的主要目的是利用先进的多模态磁共振成像（MRI）技术、X染色体起源父母分析和认知行为评估来阐明X单体和X连锁印记对大量患有TS、雌激素前替代的年轻女孩的神经发育和神经功能的影响。一个多层次，跨学科的方法被提出，利用这个研究团队在行为神经遗传学，认知神经科学，遗传学和神经影像学方面的专业知识，以及在斯坦福大学医学院现有的最先进的基础设施。拟议研究的总体目标是为将来设计早期和更有效的TS女孩干预措施提供启示。此外，这些结果将对理解遗传和表观遗传对人类大脑发育和神经功能组织的影响具有更广泛的意义。

DESCRIPTION (provided by applicant): Turner syndrome (TS) is a very common genetic disorder characterized by absence of X chromosomal material in a phenotypic female. The physical phenotypic features of TS are well-characterized, with short stature and gonadal dysgenesis being the most frequently observed. Cognitively, individuals with TS typically demonstrate normal global intellectual functioning with strengths in the verbal domain; however, many show significant deficits in visuospatial and executive functioning as well as psychosocial skills, particularly, face and emotion processing. The neural correlates of this TS cognitive-behavioral phenotype have recently begun to be explored, including neuroimaging studies of brain structure and function. However, the ability to gain meaningful insights from these studies has been limited by small sample size, large age ranges of the participants, and heterogeneity in exogenous hormone treatment status. Additionally, the impact of genetic effects such as X chromosome imprinting, on neural function and cognitive-behavioral outcome in TS, have not yet been adequately examined. Accordingly, the primary objective of this project is to use advanced, multi-modal magnetic resonance imaging (MRI) techniques, analyses of X chromosome parent-of-origin and cognitive-behavioral assessment to elucidate the effects of X monosomy and X-linked imprinting on neurodevelopment and neural function in a large cohort of young girls with TS, pre-estrogen replacement. A multi-level, cross- disciplinary approach is proposed, capitalizing on this team of investigators' expertise in behavioral neurogenetics, cognitive neuroscience, genetics and neuroimaging, as well as on the state-of the-art infrastructure available at Stanford University School of Medicine. The overarching goal of the proposed research is to generate results with implications for the design of early and more effective interventions for girls with TS in the future. In addition, these results will have broader implications for understanding genetic and epigenetic influences on brain development and organization of neural function in humans.