不明原因智力障碍/脑发育迟缓患儿染色体亚端粒重组突变的检测  

Detection of subtelomeric rearrangements in patients with idiopathic mental retardation/developmental delay

作　　者：吴晔[1] 姜玉武[1] 王小竹[2] 王慧芳[1] 王静敏[1] 杨艳玲[1] 秦炯[1] 钟南[2] 吴希如[1] 

机构地区：[1]北京大学第一医院儿科,100034 [2]北京大学医学遗传中心

出　　处：《中华儿科杂志》2007年第12期906-911,共6页Chinese Journal of Pediatrics

基　　金：教育部留学回国人员科研启动基金;北京大学第一医院留学回国基金

摘　　要：目的联合应用多重连接依赖的探针扩增法和荧光原位杂交法检测染色体亚端粒重组,进行不明原因智力障碍/脑发育迟缓(mental retardation/developmental delay,MR/DD)的病因学研究。方法入选病例必须满足:①中～重度 MR/DD;②无明确围产期异常病史;③无明确生后中毒、缺氧、中枢神经系统感染及头颅外伤等病史;④常规核型分析显示正常;⑤头颅影像及尿有机酸、氨基酸分析未提示典型遗传代谢性疾病或神经变性病;⑥男性患儿 FMR1基因检测未提示脆性 X 综合征。并至少符合以下条件之一:①MR 家族史阳性;②反复流产或围产期死亡家族史阳性;③体格发育异常;④面部畸形;⑤非面部畸形或发育异常。联合应用多重连接依赖的探针扩增法过筛和荧光原位杂交技术验证对患儿及父母标本进行染色体亚端粒重组检测。结果入组39例中发现4例阳性病例,重组分别为:①新发 der(2)t(2;4)(pter;pter),文献未见报道;②新发8pter 缺失,国外曾有报道,但临床表型不同;③新发15q11.2缺失,属中间重组,结合患儿临床表型,Angelman 综合征可能性大;④新发11qter 缺失,文献未见报道。结论首次报道2种新重组,其新发出现提示致病性可能性大;染色体亚端粒重组是遗传性 MR/DD 的重要病因,临床表型差异大,对原因不明的常规染色体检查无异常的 MR/DD 患者均应进行检测,联合应用多重连接依赖的探针扩增法和荧光原位杂交法是相对经济的确诊手段。Objective To detect subtelomeric rearrangement in patients with idiopathic mental retardation/developmental delays （MR/DD） and to provide new methods and evidence for the etiologic diagnosis of MR/DD in China. Methods 1. Inclusion criteria： ① Moderate to severe MR/DD; ② no definite perinatal brain injury; ③ no toxication, hypoxia, infection of central nervous system and cranial trauma; ④ routine karyotyping is normal; ⑤no evidence of typical inherited metabolic disorder or specific neurodegenerative disorders from cranial neuro-imaging and blood/urinary metabolic diseases screening; ⑥ no mutation of FMR1 gene in male patients plus one of the following criteria： ①positive family history of MR; ② positive family history of miscarriages and perinatal deaths; ③abnormal growth; ④ facial and nonfacial dysmorphism. 2. Multiplex ligation-dependent probe amplification （MLPA） and fluorescence in situ hybridization （FISH） were applied to detect subtelomeric rearrangements in patients and their parents. Results Four cases were identified from 39 selected cases with subtelomeric rearrangements （10%）, including der（2）t（2;4） （pter; pter）, llqter del, 8pter del, and 15pll. 2 del. The first two abnormalities of chromosome subtelomeric regions have not been reported yet. All these cases had some small dysmorphologies, such as microcephaly, hypertelorism, low nasal bridge, and three of them had hypotonia. One case had recurrent seizure and abnormal behavior （ laughter not associated with happiness） , and another case with dysgenesis of corpus callosum and septum pellucidum. Family and perinatal histories were normal for all cases. All chromosome rearrangements were de novo which were not from the parents with normalphenotype. It indicated that all these abnormal rearrangements should be responsible for the mental retardation phenotype of these patients. The phenotype of case 4 was similar to Angelman syndrome, his deletion was actually a kind of interstitial rearrangements. It

关 键 词：精神发育迟滞 染色体结构 端粒 重组 遗传 DNA探针 原位杂交 荧光 

分 类 号：R748[医药卫生—神经病学与精神病学]