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，影响总人口的2-3%。X连锁ID （XLID）疾病是由X染色体上的基因缺陷引起的，每1000名男性中就有1.7人患有这种疾病。身份证患者需要长期的家庭参与、医疗护理和社会服务，随之而来的是巨大的负担和费用。XLID是一组具有重要医学意义和生物学意义的疾病，使用传统遗传方法进一步了解其分子基础的前景很低。X染色体完整序列的可用性和下一代测序方法的巨大能力为鉴定这种高度异质性疾病的遗传基础提供了令人兴奋的新机会。事实上，男性只有一条X染色体，这使得这些疾病对大规模测序方法特别有吸引力。通过下一代测序和基因表达分析，本研究拟(1)从35个已知的X连锁ID实体中获得先显子中所有已识别的、功能重要的X染色体常染色质部分的DNA序列，(2)鉴定至少15个新的XLID基因，(3)建立本项目发现的新XLID基因的基因型/表型相关性。鉴定导致XLID的基因对于临床诊断、咨询、预防、临床管理以及合理开发有效的新疗法至关重要。了解ID的发病机制将为人类认知功能正常发展的机制提供有价值的见解。我们预计，本研究结果将导致(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)新型分子诊断方法；(3)创新疾病防治战略；(4)对受影响的个人、家庭和社会造成的重大和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.