Genetics of Turner Syndrome Neurocognitive Phenotype

描述（由申请人提供）：特纳综合征（TS）是一种人类遗传疾病，涉及缺乏全部或部分X染色体的女性。TS的典型特征包括身材矮小、不孕症和解剖异常。最近，非语言领域的特征性神经认知缺陷，如视觉空间能力，已被认为是该综合征的一部分。我们最初的资助计划是通过收集大量具有异质X染色体缺失的受试者，使用分子方法绘制缺失，并彻底分析相关表型，来绘制负责特定TS认知和身体特征的位点。严格的统计分析表明，X染色体短臂某些区域的缺失与特定的TS表型相关，包括神经认知缺陷、身材矮小和卵巢功能衰竭。表型的认知和生理方面是可分离的。我们将负责TS神经认知表型主要组成部分的基因位置缩小到远端短臂（Xp）的间隔，仅跨越X染色体的约1%。同样的间隔先前已被证明包含一种称为SHOX的基因，该基因的缺失或突变会导致身材矮小和其他TS骨骼异常。根据Williams综合征（另一种复杂的遗传疾病，具有典型的身体和认知表型）的范例，我们推断TS代表了与X染色体缺失相关的遗传和表型连续体。此外，与SHOX缺失相关的物理表型可以用来确定在TS神经认知关键区及其周围有少量远端Xp缺失的受试者群体，而不会影响他们的神经认知表型。精细绘制这些受试者的缺失将使我们能够将TS神经认知关键区域缩小到一个特定的基因。此外，表征SHOX点突变或远端Xp缺失仅限于SHOX的受试者的神经认知特征将使我们能够严格测试这种已知的TS基因是否也在神经认知表型中发挥作用。该研究利用了我们现有的临床合作以及达拉斯和费城的shox相关疾病的大量转诊人群，以获得不相关的远端Xp缺失受试者的足够样本量，以进行严格的统计分析。该项目将结合受试者的分子特征和详细的认知评估，以阐明SHOX或其他假常染色体基因缺陷在TS神经认知表型中的作用。

DESCRIPTION (provided by applicant): Turner syndrome (TS) is a human genetic disorder involving females who lack all or part of one X chromosome. Classic TS features include short stature, infertility, and anatomic abnormalities. More recently, characteristic neurocognitive deficits in nonverbal domains such as visual-spatial abilities have been recognized as part of the syndrome. Our original grant proposed to map loci responsible for specific TS cognitive and physical features by collecting a large number of subjects with heterogeneous X chromosome deletions, mapping the deletions using molecular methods, and thoroughly analyzing associated phenotypes. Rigorous statistical analysis showed that deletions of certain regions of the short arm of the X chromosome were associated with specific TS phenotypes, including neurocognitive deficits, short stature, and ovarian failure. Cognitive and physical aspects of the phenotype were dissociable. We narrowed the location of gene(s) responsible for a major component of the TS neurocognitive phenotype to an interval of the distal short arm (Xp) spanning only ~1% of the X chromosome. This same interval has been previously shown to contain a gene termed SHOX, deletions or mutations of which cause short stature and other TS skeletal abnormalities. Following the paradigm of Williams syndrome, another complex genetic disorder with characteristic physical and cognitive phenotypes, we reasoned that TS represents a genetic and phenotypic continuum associated with X chromosome deletions. Furthermore, physical phenotypes associated with SHOX deletions could be used to ascertain a population of subjects with small distal Xp deletions in and around the TS neurocognitive critical region without bias with regard to their neurocognitive phenotypes. Fine-mapping these subjects' deletions will allow us to narrow the TS neurocognitive critical region to a specific gene(s). Furthermore, characterizing the neurocognitive profile of subjects with SHOX point mutations or distal Xp deletions limited just to SHOX will allow us to critically test whether this known TS gene also plays a role in the neurocognitive phenotype. The proposed study takes advantage of our existing clinical collaborations as well as large referral populations for SHOX-associated disorders in Dallas and Philadelphia to obtain a sufficient sample size of unrelated distal Xp deletion subjects for rigorous statistical analyses. The project will combine molecular characterization of subjects with detailed cognitive evaluations to elucidate the role of SHOX or other pseudoautosomal gene deficiencies in the TS neurocognitive phenotype.