Genetics of Turner Syndrome Neurocognitive Phenotype

特纳综合征神经认知表型的遗传学

• 批准号: 6784147
• 负责人: Andrew R. Zinn
• 金额: $ 49.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784147
• 关键词: Turner' s syndrome; aneuploidy; behavioral /social science research tag; body physical characteristic; chromosome deletion; chromosome disorders; clinical research; cognition disorders; cytogenetics; female; fluorescent in situ hybridization; genetic mapping; human subject; karyotype; neuropsychological tests; neuropsychology; phenotype; sex chromosomes; sex linked trait; tissue /cell culture

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.

描述（由申请人提供）：特纳综合征（TS）是一种人类遗传疾病，涉及女性缺乏全部或一部分X染色体的女性。经典的TS特征包括身材矮小，不育和解剖异常。最近，非语言领域（例如视觉空间能力）中的特征性神经认知缺陷已被认为是综合征的一部分。我们的原始赠款建议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，并彻底分析相关的表型，从而绘制负责特定TS认知和物理特征的基因座。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TS表型有关，包括神经认知缺陷，身材矮小和卵巢衰竭。表型的认知和物理方面是可以解散的。我们将负责TS神经认知表型的主要组成部分的基因的位置缩小到仅X染色体〜1％的远端短臂（XP）的间隔。先前已证明相同的间隔包含称为Shox，缺失或突变的基因，这会导致身材矮小和其他TS骨骼异常。遵循威廉姆斯综合征的范式，这是另一种具有特征性物理和认知表型的复杂遗传疾病，我们认为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在TS神经认知临界区域内和周围远端XP缺失的受试者，而其神经认知表型没有偏见。精细映射这些受试者的缺失将使我们能够将TS神经认知临界区域缩小到特定基因。此外，表征具有SHOX点突变或远端XP缺失受试者的神经认知谱，仅限于Shox将使我们能够批判性地测试该已知的TS基因是否也在神经认知表型中起作用。拟议的研究利用了我们现有的临床合作以及达拉斯和费城与SHOX相关疾病的大量推荐人群，以获得足够的无关远端XP XP缺失受试者的样本大小，以进行严格的统计分析。该项目将结合受试者的分子表征和详细的认知评估，以阐明Shox或其他假阳性体基因缺陷在TS神经认知表型中的作用。