Jacobsen综合征2例诊断及染色体缺失区域的定位分析  

Diagnosis and fine location of deletion region in Jacobsen syndrome patients

作　　者：季涛云[1] 陈红梅[2,3] 吴晔[1] 肖静[4] 王静敏[1] 李洁[1] 姜玉武[1] 

机构地区：[1]北京大学第一医院儿科,北京100034 [2]内蒙古自治区医院儿科,呼和浩特010017 [3]北京大学第一医院 [4]首都医科大学附属北京儿童医院神经内科,北京100045

出　　处：《中国实用儿科杂志》2010年第8期602-606,共5页Chinese Journal of Practical Pediatrics

基　　金：国家重点基础研究发展计划(973);北京市自然科学基金重点项目

摘　　要：目的诊断并精细定位2例Jacobsen综合征(JBS)染色体缺失区域,探讨JBS基因型与表型的关系。方法 2006年12月至2009年7月北京大学第一医院儿科神经门诊以及北京市儿童医院神经内科门诊就诊的中重度脑发育迟缓/智力低下(developmental delay/mental retardation,DD/MR)患儿451例,采集患儿及其父母外周血,提取基因组DNA,通过多重连接依赖性探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)对亚端粒区拷贝数进行筛查,并用2种SALSA MLPA试剂盒(P070和P036)进行相互验证,阳性结果者进一步对其父母标本进行检测了解是否为新发;对MLPA检测阳性的新发拷贝数异常者行Affymetrix SNP6.0芯片检测以进一步验证,并精确定位明确拷贝数异常的片段范围。结果 451例患儿中发现2例存在11q远端缺失,临床符合JBS,均表现有严重脑发育迟缓、小头畸形和面容异常,均无血小板减少。病例1为低出生体重儿,同时患脑白质髓鞘化延迟;病例2合并先天性心脏病并有骨骼畸形。2例患儿11号染色体缺失片段长度分别为4.1Mb和12.8Mb,其中4.1Mb是目前报道的最小缺失区域。结论 JBS导致DD/MR的关键区域可能位于接近亚端粒区4.1Mb范围内,SNX19、THYN1、OPCML、NCAPD3和NTM可能为其关键的致病基因;导致颅面部畸形的重要区域可能位于在11号染色体上130.3～134.4Mb区域;导致心脏结构异常的关键区域可能位于125.8～130.4Mb区域。其基因型与表型的确切关系,还有待大样本分析并确认导致DD/MR的致病基因。Objective To first diagnose and fine map the chromosome deletion regions of two children with Jacobsen syndrome by Affymetrix SNP 6.0 chip in China and roughly analyze the correlation between phenotype and genotype. Methods Genomie DNA of each index patient and his/her parents was extracted from peripheral blood. Screening of subtelomeric rearrangements was carried out in all patients by MLPA （P070）. For each patient with a positive result, a subsequent second-stage test was performed with another MLPA kit （P036）. The parents of patients who had positive resuits confirmed by the second kit were tested to assess whether the genetic aberrations were de novo or inherited. If the subtelomeric aberrations were de novo, then we used the Affymetrix genome-wide human SNP array 6.0 to confirm and accurately define the exact size of each subtelomerie aberrant region. Results We found that two patients presented with severe DD, microcephaly, and facial dysmophism. Patient 1 had low birth weight and white matter with delaying of myelinization, and patient 2 had congenital heart disease and skeletal deformity. No patient was with thrombocytope-nia. We found that the sizes of the deletions were 4.1 Mb andl2.8 Mb respectively. The 4.1 Mb deletion was smaller than any other region previously reported for this syndrome. Conclusion The critical region underlying DD, MR is probably distal part within 4.1Mb to the telomere, and SNX19, THYNI, OPCML, NCAPD3 and NTM might be candidate genes. One of the critical regions for craniofacial abnormalities may be within 130.3-134.4Mb in chromosome 1 lq. （3） The critical region related to congenital heart malformations may be within 125.8Mb-130.4Mb in chromosome 1 lq. However, we realize that this study is limited by the small sample of cases presented and hope that in the future more Chinese JBS patients will be reported to elucidate the spectrum and relationship of the phenotype and genotype of JBS in China.

关 键 词：Jacobsen综合征 11q亚端粒缺失 脑发育迟缓 智力障碍 

分 类 号：R72[医药卫生—儿科]