发育性癫痫性脑病75型家系的遗传学分析

Genetic analysis of a pedigree with premature epileptic encephalopathy type 75

目的分析1个发育性癫痫性脑病75型(developmental and epileptic encephalopathy 75, DEE75)家系3例患儿的临床特征,探讨该家系线粒体脯氨酰tRNA合成酶2(prolyl-tRNA synthetase 2, mitochondrial,PARS2)基因突变情况。方法分析该DEE75家系3例患儿(先证者及其哥哥、弟弟)的临床资料;对先证者及其父母进行全外显子组测序,对鉴定出的可疑致病突变在先证者及其弟弟、父母中采用Sanger测序法进行验证;对未报道的可疑致病突变进行生物信息学分析、蛋白质结构模型预测。结果该家系3例患儿均存在小头畸形、发育迟缓、智力障碍等表型,先证者哥哥有癫痫表现。先证者及其弟弟均存在PARS2基因c.283G>A(p.Val95Ile)、c.664A>G(p.Thr222Ala)及c.1059A>C(p.Glu353Asp)复合杂合错义突变,先证者母亲存在c.283G>A错义突变,先证者父亲存在c.664A>G及c.1059A>C错义突变。生物信息学分析显示c.664A>G及c.1059A>C为未报道的可能有害突变。蛋白质结构预测显示c.664A>G可能破坏蛋白质结构和功能而致病,c.1059A>C对蛋白质结构无明显影响。结论 PARS2基因c.283G>A及c.664A>G复合杂合错义突变可能是该家系DEE75患儿的致病原因。

Objective To analyze the clinical characteristics of three children from a pedigree of developmental and epileptic encephalopathy type 75(DEE75), and discuss the mutation of its PARS2 gene. Methods The clinical data of the proband, his elder brother and younger brother in the DEE75 family were analyzed. Whole exome sequencing was performed in the proband and his parents. The identified possible pathogenic mutations were verified in the proband, his younger brother and his parents by Sanger sequencing, and the unreported possible pathogenic mutations were verified by bioinformatics analysis software and protein structure model. Results These three children in this family all had microcephaly, developmental delay, mental retardation and other phenotypes. Among them, the elder brother of the proband had manifestation of epilepsy. c.283 G>A(p.Val95 Ile), c.664 A>G(p.Thr222 Ala) and c.1059 A>C(p.Glu353 Asp) missense mutations were detected in the PARS2 gene of the proband and his younger brother. The mother of the proband had c.283 G>A mutation, and the father of the proband had c.664 A>G and c.1059 A>C mutations. The c.664 A>G and c.1059 A>C were the unreported missense mutations. c.664 A>G, but not c.1059 A>C, caused disease by destroying protein structure and function. Conclusion PARS2 gene c.283 G>A and c.664 A>G compound heterozygous missense mutations might be the genetic cause of DEE75 in these three children of this family.