孤独症相关基因CNTNAP2的遗传变异分析

Association of genetic variations of CNTNAP2 gene with autism

目的:研究在中国南方汉族人群中CNTNAP2基因遗传变异与孤独症的相关性。方法:收集45个孤独症患儿及其核心家系成员血样,对CNTNAP2基因序列进行直接测序分析,比对识别出稀有突变、短的插入缺失和单核苷酸多态性(SNP),并将它们的等位基因频率和基因型与千人基因组计划数据信息进行统计比较,发现关联性的位点,建立在核心家系中的遗传传递模式。同时利用计算机辅助分析这些遗传变异对蛋白质结构和功能的影响。结果:共发现4个稀有突变、3个短的插入缺失和13个SNP位点,其中包括两个错义突变p.747A>V和p.1102V>I。家系传递分析发现3个新生突变及4个遗传自父母的风险因子。rs6973990G>T等位基因的频率在患者中显著低于健康人群(χ2=9.356,P=0.002)。另有5个SNP的基因型在等位基因效用显性模型或隐性模型中发现与孤独症具有显著相关性(P<0.05)。软件分析的结果提示p.747A>V的突变对蛋白质结构和功能可能有害。结论:中国南方汉族人群CNTNAP2基因变异与孤独症发病显著相关。

Objective： To explore the association of genetic variations in CNTNAP2 gene with autism in southern Chi- nese Han population. Methods： Blood samples from 45 patients with autism and their core family members were re cruited in this study. The exons and their flanking regions of CNTNAP2 gene were directly sequenced. After aligning the sequence from 45 patients with autism and their core family, DNA variants were identified, including rare muta- tions, indels and SNPs, and their allele frequency and genotypes were compared with those obtained from the 1000 C-e nome Project. The transmission of these variations were also studied in the core family. Finally, computational algo rithms were employed to estimate deleterious effects of these variations to the protein structure and function. Results： A total of 4 rare mmations, 3 indels and 13 SNPs were identified from patients with autism, including 2 missense mu- tations p.747 A^V and p.1102 V）〉I. 3 of these mutations and indels were de novo origination, the other four were in- herited from parents. The allele frequency of rs6973990 （}~T was diverse between patients with autism and healthy controls （Xe =9.356, P=0.002）. Moreover, 5 SNPs were calculated to be significantly different in an effective allele dominant model or recessive model respectively （P 〈0.05）. In addition, computer--assistant analysis indicated that the p.747 A^V mutation might be functionally deleterious. Conclusion： Genetic variations of CNTNAP2 gene are perhaps involved in the pathogenic mechanism of autism in southern Chinese Han population.