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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。
AIM: To investigate the association of genetic variants of CNTNAP2 with autism in Chinese Han population in South China. Methods: A total of 45 children with autism and their nuclear family members were collected for blood sequencing. The sequence of CNTNAP2 gene was directly sequenced, and rare mutations, short insert deletions and single nucleotide polymorphisms (SNPs) were identified. Their allelic frequencies and genotypes were compared statistically with thousands of genome-project data messages to find sites of relevance for establishing patterns of inheritance of transmission in nuclear families. At the same time using computer-aided analysis of these genetic variations on protein structure and function. RESULTS: Four rare mutations, three short deletions and 13 SNPs were found, including two missense mutations, p.747A> V and p.1102V> I. Analysis of pedigree transmission revealed three newborn mutations and four risk factors inherited from parents. The rs6973990G> T allele frequency was significantly lower in patients than in healthy people (χ2 = 9.356, P = 0.002). Another five genotypes of SNPs were found to be significantly associated with autism in the dominant or recessive model of allele effects (P <0.05). The results of the software analysis suggest that mutations at p.747A> V may be detrimental to the structure and function of the protein. Conclusion: The variation of CNTNAP2 gene in Chinese Han population in South China is significantly associated with the onset of autism.