以先天性心脏病为主要表现的8p缺失伴重复新生儿全基因组拷贝数变异分析二例

Analysis of genomic copy number variations in two unrelated neonates with 8p deletion and duplication associated with congenital heart disease

目的 寻找8号染色体参与心脏发育的关键区域.方法 采用Affymetrix SNP芯片技术,对2例多发畸形新生儿病例进行全基因组拷贝数变异（CNVs）筛查,经过筛选得到罕见潜在致病性CNVs,将CNVs片段结合患儿的表型进一步与DECIPHER数据库、ISCA数据库中的病例信息进行比对.结果 （1）2例共检测到潜在致病性CNVs 11个,大小为546.6～27 892 kb,全部集中在8号染色体短臂,邻近的CNV合并后得到4个不同区域.例1的2个CNVs分别为8p23.3-8p23.1（387 912～11 506 771 bp）缺失和8p23.1-8p11.1（11 508 387～43 321 279 bp）重复;例2的2个CNVs分别为8p23.3-8p23.1（46 385 ～7 809 878 bp）缺失和8p23.1-8p11.2（12 260 914 ～40 917 092 bp）重复.（2）与数据库中的病例信息比对结果：例1为严重心脏畸形,其缺失的8p23.1的7 809 878 ～11 506 771 bp区域内包含心脏发育相关基因SOX7,重复区段内包含GATA4,荧光定量PCR验证例1的SOX7拷贝数低于正常,GATA4拷贝数高于正常.例2的SOX7和GATA4拷贝数正常.结论 8p23.1上7 809 878～ 11 506 771 bp区段与心脏发育异常相关,为参与心脏发育的关键区域,SOX7拷贝数减低、GATA4拷贝数增加可能为导致心脏畸形的原因之一.

Objective To screen for genomic copy number variations （CNVs） in two unrelated neonates with multiple congenital abnormalities using Affymetrix SNP chip and try to find the critical region associated with congenital heart disease.Method Two neonates were tested for genomic copy number variations by using Cytogenetic SNP chip.Rare CNVs with potential clinical significance were selected of which deletion segments＇ size was larger than 50 kb and duplication segments＇ size was larger than 150 kb based on the analysis of ChAs software,without false positive CNVs and segments of normal population.The identified CNVs were compared with those of the cases in DECIPHER and ISCA databases.Result Eleven rare CNVs with size from 546.6-27 892 kb were identified in the 2 neonates.The deletion region and size of case 1 were 8p23.3-p23.1 （387 912-11 506 771 bp） and 11.1 Mb respectively,the duplication region and size of case 1 were 8p23.1-p11.1 （11 508 387-43 321 279 bp）and 31.8 Mb respectively.The deletion region and size of case 2 were 8p23.3-p23.1 （46 385-7 809 878 bp） and 7.8 Mb respectively,the duplication region and size of case 2 were 8p23.1-p11.21 （12 260 914-40 917 092 bp）and 28.7 Mb respectively.The comparison with Decipher and ISCA databases supported previous viewpoint that 8p23.1 had been associated with congenital heart disease and the region between 7 809 878-11 506 771 bp may play a role in the severe cardiac defects associated with 8p23.1 deletions.Case 1 had serious cardiac abnormalities whose GATA4 was located in the duplication segment and the copy number increased while SOX7 was located in the deletion segment and the copy number decreased.Conclusion The region between 7 809 878-11 506 771 bp in 8p23.1 is associated with heart defects and copy number variants of SOX7 and GATA4 may result in congenital heart disease.