儿童孤独症患者γ-氨基丁酸(GABA)A类受体基因簇的罕见变异

Rare variations in gamma-aminobutyric acid type A(GABA_A) receptor genes cluster in children with autism

目的:探讨儿童孤独症患者染色体15q12区域γ-氨基丁酸A类受体基因簇是否存在可能致病的罕见变异。方法:对96例符合DSM-IV孤独症诊断标准的中国汉族儿童孤独症患者γ-氨基丁酸A类受体基因簇进行靶向测序,采用Sanger测序法进行验证。进一步扩大样本筛查罕见变异,通过连续性校正χ2检验比较罕见变异的分布频率在384例儿童孤独症病例组和384例正常对照组的差异。结果:96例儿童孤独症患者靶向测序发现8个罕见变异,包括GABRG3基因的2个罕见错义突变[rs201602655(p. Val233Met)和rs201427468 (p. Pro365Ser)]和GABRB3基因非编码区的6个罕见突变。Sanger测序验证后进一步扩大样本,rs201602655杂合型变异在孤独症组出现的频率高于正常对照组(2. 1%vs. 0. 3%,P <0. 05)。功能预测提示rs201602655罕见变异为有害突变,可能导致GABRG3蛋白质的异常。结论:GABRG3基因在儿童孤独症存在影响氨基酸改变的罕见变异,是孤独症的易感基因可能参与孤独症的致病。

Objective:To investigate whether there are pathogenic rare variants of gamma-aminobutyric acid type A(GABA A)receptor genes cluster in chromosome 15q12 in children with autism.Methods:The GABA A receptor genes cluster in 96 Chinese Han autistic patients who fulfilled the criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition were sequenced by target sequencing and validated the rare variants using Sanger sequencing.Furthermore,the sample size was expanded.The Continuity correction chi-square test was used to compare the difference of frequencies of these rare variations between 384 children with autism and 384 normal controls.Results:Through the target sequencing,8 rare variants were found in the 96 autistic patients,including two rare missense mutations in GABRG3(rs201602655(p.Val233Met),rs201427468(p.Pro365Ser))and 6 rare mutations in noncoding regions of GABRB3.After validation of these results by Sanger sequencing and expansion of sample size,the frequency of heterozygous rs201606255 in autistic children was higher than that in controls(2.1%vs.0.3%,P<0.05).Functional prediction suggested that rs201602655 was a deleterious mutation that might affect the function of GABRG3.Conclusion:GABRG3 harbors rare mutations that changes amino acid in autistic children.GABRG3 may be a susceptible gene for autism and is involved in the pathogenesis of autism.