一例Okur-Chung神经发育障碍综合征患儿的CSNK2A1基因变异分析

Identification of a novel de novo variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome

目的对1例确诊Okur-Chung神经发育障碍综合征(Okur-Chung neurodevelopmental syndrome,OCNS)患儿的CSNK2A1基因进行变异分析,明确其遗传学病因。方法应用全外显子基因组测序法检测相关基因变异,并通过Sanger测序法验证变异。对可疑变异进行生物信息学预测分析其致病性。结果经全外显子基因组测序分析发现,患儿CSNK2A1基因上第4外显子存在一个c.149A>G(p.Tyr50Cys)杂合错义变异,该变异为新发变异,且为未报道过的新变异。c.149A>G(p.Tyr50Cys)变异经PolyPhen-2、Mutation Taster、SIFT等预测软件预测,结果均提示为有害变异,并经HomoloGene及PubMed BLAST系统分析CSNK2A1基因编码的CK2α蛋白第50位Tyr在各种属间均高度保守,该氨基酸的改变可通过影响ATP Banding Loop、tetramer interface两个结构域的形成而导致CK2α蛋白结合ATP及形成异构四聚体功能发生障碍。同时经Swiss PDB viewer软件对蛋白3D结构建模分析发现,该氨基酸的改变可导致CK2α蛋白原有空间结构发生改变,原有蛋白功能丧失。结论CSNK2A1基因c.149A>G(p.Tyr50Cys)变异可能为该患儿罹患OCNS的致病原因。

Objective To analyze pathogenic variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome(OCNS).Methods The 8-year-old boy presented with growth retardation,intellectual disability and spells of breath holding.With genomic DNA extracted from peripheral blood samples of the patient and his parents,whole exome sequencing was carried out.Putative pathogenic variants were verified with Sanger sequencing.The nature and impact of detected variants were predicted through bioinformatic analysis.Results A novel de novo missense variant c.149A>G(p.Tyr50Cys)of the CSNK2A1 gene was identified,which was unreported previously.The variant was predicted to be pathogenic by PolyPhen-2,Mutation Taster and SIFT software.Based on a HomoloGene system,50 loci within the CK2αprotein are highly conserved.The change of amino acid(Cys)at position 50 has destroyed the ATP binding loop domain,causing serious damage to its function.As predicted by a Swiss PDB viewer,the variant can significantly alter the spatial structure of CK2α,resulting in loss of protein function.Conclusion The patient’s condition may be attributed to the novel de novo missense variant c.149A>G(p.Tyr50Cys)of the CSNK2A1 gene.