通过分析LOH探究智力障碍的致病基因变异

Intellectual disability (ID) is presented with significant defects in intellectual functioning and adaptive ability. This neurological disorder results in major limitation in personal life and also heavy burden on the family and society. Nearly two thirds of ID are attributed by genetic factors. Precise genetic diagnosis is crucial for the disease classification, prognosis, proper treatment of the condition, and also the management of recurrent risk in the family. Currently whole-genome microarray is the first-tier test for unexplained intellectual disability, which identifies Copy Number Variations (CNVs), but over 70% of ID patients remain undiagnosed after the microarray analysis. We performed a pilot study on the SNP microarray data from patients without clear diagnosis, and found that CNV-neutral Loss of Heterozygosity (LOH) regions exist in some patients. These LOH regions are at high risk of harboring autosomal recessive mutations. We propose to analyze these LOH regions and select some for sequencing, including those differ significantly from the population and possess genes that are likely related to ID. All the sequencing variants will go through filtering, and the potential pathogenic variants will be selected for validation and further functional analysis. This project aims at exploring SNP information that has been obtained but not utilized yet in clinical microarray tests, establishing a genetic diagnostic pipeline based on LOH analysis, improving the etiology-based diagnosis of ID and providing potential biological targets for medical intervention.

智力障碍表现为认知功能及适应能力的显著缺陷，严重影响个人生活并给家庭及社会造成沉重负担。近2/3的智障发生与遗传因素相关，明确的分子遗传学诊断对于疾病的分型、预后、合理治疗以及再生育复发风险的控制极为关键。目前对于不明原因智障的遗传检测首推全基因组芯片扫描，可以检测出拷贝数变异，但仍有逾70%的患者在芯片扫描后无法获得明确诊断。本课题组对无明确诊断的病人芯片结果进行SNP分析后发现，部分病人存在拷贝数正常但杂合性丢失(LOH)的区域，这些区域极可能存在隐性遗传疾病的纯合基因突变。本课题拟对这些LOH区域进行分析，选择出人群中罕见的LOH区域，对其中存在较高致病风险的基因进行测序，筛选出潜在的基因突变，并研究其对功能的影响。本课题旨在发掘临床芯片检测中已取得但未被利用的SNP信息，建立一种基于LOH分析的致病基因变异检测流程，提高智障的病因学诊断水平，并为智障的医疗干预提供生物学靶点。

近2/3的智障发生与遗传因素相关，明确的分子遗传学诊断对于疾病的分型、预后、合理治疗以及再生育复发风险的控制极为关键。目前对于不明原因智障的遗传检测首推全基因组芯片扫描，可以检测出拷贝数变异，但仍有逾70%的患者在芯片扫描后无法获得明确诊断。本课题组对无明确诊断的病人芯片结果进行SNP分析后发现，部分病人存在拷贝数正常但杂合性丢失(LOH)的区域，这些区域极可能存在隐性遗传疾病的纯合基因突变。本课题对这些LOH区域进行分析，选择出人群中罕见的LOH区域，对其中存在较高致病风险的基因进行测序，试图发掘其中的致病性变异。.本课题分析了逾3065例芯片样本，获得117条罕见LOH，对其中36例样本测序后发现8例样本携致病性变异。其中2例样本中发现位于LOH区域的纯合突变，分别位于ATM及SURF1基因上；另外6例样本中发现的致病性突变位于LOH区域之外，分别位于AMPD2，CTNNB1，SLC9A6，DDX3X，KMT2D及RPS6KA3基因。在另外28例样本中，测序后并未发现与患者表型相关的致病性变异。本项目结果提示对携LOH的芯片阴性样本进行测序分析，可能提升22.2%的诊断率；若仅对其中LOH区域进行分析，可能提升5.6%的诊断率。.综上，本课题发掘了临床芯片检测中已取得但未被利用的SNP信息，建立了一种基于LOH分析的致病基因变异检测流程，提高了智障的病因学诊断水平。

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