一例重型Cornelia de Lange综合征患者的NIPBL基因变异分析

目的分析1例重型Cornelia de Lange综合征(Cornelia de Lange syndrome,CdLS)患儿的NIPBL基因变异,明确其遗传学病因。方法提取患儿及其父母外周血中DNA物质,应用全外显子基因组测序法检测相关基因变异,应用Sanger测序法验证变异。对可疑变异进行生物信息学预测。结果经全外显子基因组测序分析并经Sanger测序验证,发现患儿NIPBL基因第9外显子存在c.1507A>G(p.Lys503Glu)杂合错义变异,该变异为新发变异,且为未报道过的新变异。经PolyPhen-2、Mutation Taster、SIFT预测软件预测c.1507A>G(p.Lys503Glu)变异为可能有害变异,并经HomoloGene系统分析NIPBL蛋白第503位Lys在各种属间均高度保守,该位点氨基酸改变可导致编码的NIPBL原有蛋白功能发生障碍。而经过PubMed BLAST系统进一步分析发现该位点氨基酸的改变可通过影响Neuromodulin_N superfamily结构域的形成来导致NIPBL蛋白功能发生障碍的。结论NIPBL基因c.1507A>G(p.Lys503Glu)错义变异可能为该患儿罹患重型CdLS的致病原因,基因变异检测结果可以为家系的遗传咨询和产前诊断提供依据。

Identification of a novel missense NIPBL variant in a juvenile with severe type of Cornelia de Lange syndrome

Objective To detect pathogenic variant in a juvenile with severe type Cornelia de Lange syndrome(CdLS).Methods A 12-year-old female presented with comprehensive developmental retardation and deformity of lower limbs.Genomic DNA was extracted from peripheral blood sample of the patient.Whole exome sequencing was performed to identify pathogenic variants.Putative variant was verified by Sanger sequencing.The impact of variants was predicted and validated by bioinformatic analysis.Results A de novo missense variant,c.1507A>G(p.Lys503Glu),was found in the NIPBL gene of the proband.The variant was unreported previously and predicted to be pathogenic by PolyPhen-2,MutationTaster and SIFT.Using HomoloGene system,the 503 loci in the NIPBL protein are highly conserved.The change of amino acid(Glu),locating in 503 locus,was found to cause the Neuromodulin_N superfamily domain destroyed,resulting in severe damage to the function of NIPBL protein.Conclusion The de novo missense variant c.1507A>G(p.Lys503Glu)of the NIPBL gene probably underlies the disease in this patient.