Genetics of Turner Syndrome Neurocognitive Phenotype

描述（由申请人提供）：特纳综合征（TS）是一种人类遗传性疾病，涉及缺乏全部或部分X染色体的女性。典型的TS特征包括身材矮小、不育和解剖异常。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。我们最初的资助建议通过收集大量具有异质性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认知和身体特征的基因座。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。表型的认知和身体方面是分离的。我们将负责TS神经认知表型的主要成分的基因的位置缩小到仅跨越X染色体的~1%的远端短臂（Xp）的间隔。先前已经证明，相同的间隔包含称为SHOX的基因，其缺失或突变导致身材矮小和其他TS骨骼异常。根据威廉姆斯综合征（另一种具有特征性身体和认知表型的复杂遗传疾病）的范例，我们推断TS代表与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用于确定TS神经认知关键区域内和周围具有小的远端Xp缺失的受试者群体，而不会对他们的神经认知表型产生偏倚。精细定位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特定的基因。此外，表征具有SHOX点突变或仅限于SHOX的远端Xp缺失的受试者的神经认知概况将使我们能够严格地测试这种已知的TS基因是否也在神经认知表型中起作用。拟定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，以获得足够的无关远端Xp缺失受试者样本量进行严格的统计分析。该项目将结合联合收割机的分子特征的主题与详细的认知评估，以阐明的作用，SHOX或其他假常染色体基因缺陷的TS神经认知表型。

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.