Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China
Diagnosis of intellectual disability/global developmental delay via genetic analysis in a central region of China
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中国中部地区智力障碍/整体发育迟缓的遗传分析诊断
DOI：
10.1097/cm9.0000000000000295
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发表时间：
2019-07-05
影响因子：
6.1
通讯作者：
Yin, Fei
中科院分区：
文献类型：
--
作者：
Liao, Li-Hong;Chen, Chen;Yin, Fei
背景：先进的技术已成为智力残疾/全面发育迟缓（ID/GDD）病因学研究的重要工具。本研究调查了遗传分析在确定病因不确定的中国中部ID/GDD患者病因学中的作用。方法：2009年3月至2017年4月对1051名6个月至18岁的ID/GDD儿童进行评估。收集基本临床表现资料，记录病因确认方法。对目标区域的外显子进行全基因组拷贝数变异（CNVs）检测和高通量测序，以确定基于遗传的病因。我们使用卡方或Fisher精确概率检验比较了不同程度ID/GDD组中用于确认ID/GDD病因的不同方法的发生率。结果：我们招募了1051名患有轻度（367例，34.9%）、中度（301例，28.6%）、重度（310例，29.5%）和重度（73例，6.9%）ID/GDD的儿童。被评估儿童发生ID/GDD的主要原因是围产期因素，如获得性脑损伤，以及单基因失衡和染色体基因突变。我们在46/96例（47.9%）重度ID/GDD患者中发现核型和/或CNVs变异，显著高于轻度和中度ID/GDD患者的34/96（35.4%）和15/96（15.6%）。病因明确的患者中有331/536例（61.8%）进行了遗传分析，病因不明的患者中有261 /515例（50.9%）进行了遗传分析（chi(2) = 12.645, P < 0.001）。通过核型分析和CNV检测的基因结构变异使确诊病因的儿童比例从51.0%增加到56.3%，第二代高通量测序使这一比例大幅增加到78.9%。发现了10个新突变，其中x -连锁基因（atp酶铜转运α和溴结构域和含有WD重复结构域3）的隐性突变和x -连锁基因（周期蛋白依赖激酶样5、原钙粘蛋白19、IQ基序和Sec7结构域2、甲基cpg结合蛋白2）的显性新杂合突变在研究中被报道。结论：本研究提示，遗传分析是提高ID/GDD患儿确诊病因比例的有效方法，尤其在病因不明的ID/GDD患儿中，值得推荐。
Background: Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay (ID/GDD). The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.Methods: We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017. Data concerning basic clinical manifestations were collected, and the method of etiology confirmation was recorded. Genome-wide copy number variations (CNVs) detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies. We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.Results: We recruited 1051 children with mild (367, 34.9%), moderate (301, 28.6%), severe (310, 29.5%), and profoundly severe (73, 6.9%) ID/GDD. The main causes of ID/GDD in the children assessed were perinatal factors, such as acquired brain injury, as well as single gene imbalance and chromosomal gene mutation. We identified karyotype and/or CNVs variation in 46/96 (47.9%) of cases in severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD of 34/96 (35.4%) and 15/96 (15.6%), respectively. A total of 331/536 (61.8%) patients with clear etiology have undergone genetic analysis while 262/515 (50.9%) patients with unclear etiology have undergone genetic analysis (chi(2) = 12.645, P < 0.001). Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0% to 56.3%, and second-generation high-throughput sequencing dramatically increased this to 78.9%. Ten novel mutations were detected, recessive mutations in X-linked genes (ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3) and dominant de novo heterozygous mutations in X-linked genes (cyclin-dependent kinase like 5, protocadherin 19, IQ motif and Sec7 domain 2, and methyl-CpG binding protein 2) were reported in the study.Conclusions: The present study indicates that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended, especially in ID/GDD children with uncertain etiology.