Identification of Novel X-linked Intellectual Disability Genes

描述（由申请人提供）：智力残疾（ID）是一种常见的残疾，影响2-3%的一般人口。由X染色体上的基因缺陷引起的X连锁ID（XLID）疾病影响1，000名男性中的1.7名。ID患者需要长期的家庭参与，医疗护理和社会服务，伴随着巨大的负担和成本。 XLID是一组具有医学重要性和生物学意义的疾病，使用传统遗传学方法对其分子基础的理解取得进一步进展的前景很低。X染色体的完整序列的可用性和下一代测序方法的巨大能力提供了一个令人兴奋的新机会，以确定这种高度异质性的疾病组的遗传基础。男性具有单个X染色体的事实使得这些疾病对于大规模测序方法特别有吸引力。 利用下一代测序和基因表达分析，本研究旨在（1）从35个已知的X连锁ID实体中获得先证者X染色体常染色质部分所有公认的功能重要片段的DNA序列，（2）鉴定至少15个新的XLID基因，（3）建立本项目中发现的新XLID基因的基因型/表型相关性。 确定导致XLID的基因对于临床诊断、咨询、预防、临床管理和合理开发有效的新治疗方法至关重要。了解ID的发病机制将为人类认知功能的正常发育机制提供有价值的见解。我们预计这项研究的结果将导致（1）新的研究项目，以了解这些XLID基因在智力功能中的功能;（2）新的分子诊断方法;（3）疾病预防和治疗的创新策略;（4）对受影响的个人，他们的家庭和社会产生重大而持久的经济和社会影响。

DESCRIPTION (provided by applicant): Intellectual disability (ID) is a common disability affecting 2-3% of the general population. X-linked ID (XLID) disorders, caused by defects of genes on the X chromosome, affect 1.7 of 1,000 males. Patients with ID require long-term family involvement, medical care and social services with enormous attendant burden and cost. XLID is a medically important and biologically significant group of disorders for which the prospects for further progress on the understanding of their molecular basis using traditional genetic approaches are low. The availability of finished sequence for the X chromosome and the enormous capability of the next generation sequencing methods offer an exciting new opportunity to identify the genetic bases of this highly heterogeneous group of disorders. The fact that males have a single X chromosome makes these disorders especially attractive targets for a large scale sequencing approach. Using next generation sequencing and gene expression analysis, this study intends to (1) obtain DNA sequence of all recognized, functionally important segments of the euchromatic portion of the X chromosome in probands from 35 known X-linked ID entities, (2) identify a minimum of 15 novel XLID genes, and (3) establish genotype/phenotype correlations for the novel XLID genes discovered in this project. Identification of genes that cause XLID is essential for clinical diagnosis, counseling, prevention, clinical management, and a rational development of effective novel treatments. Understanding the pathogenesis of ID will provide valuable insight into the mechanisms for normal development of human cognitive functions. We anticipate that the results of this study will lead to (1) new research projects to understand the function of these XLID genes in intellectual function; (2) novel molecular diagnostic methods; (3) innovative strategies for disease prevention and treatment; and (4) major and lasting economic and social impacts on the affected individuals, their families, and society.