一例新生突变所致Glass综合征的遗传学分析

Genetic analysis of a case of Glass syndrome caused by de novo mutation

目的对一个Glass综合征家系的致病基因变异位点进行检测并对其进行遗传学分析。方法对先证者进行临床检查和全外显子组测序;对其家系成员通过PCR-Sanger测序验证可疑突变位点;用I-TASSER蛋白结构与功能分析软件对候选致病基因所编码的蛋白进行生物信息学分析。结果先证者临床表现为全面性发育迟缓,主要包括牙齿异常、共济失调、不会听指令;脑电图提示多灶性棘波、棘慢波、多棘慢波发放,左侧及睡眠期著等。检出先证者具有SATB2基因(NM_015265)c.1165C>T(p.R389C)新生杂合错义突变,其父母均未检出该突变;蛋白结构生物信息分析表明,p.R389C错义突变可导致蛋白的配体结构域发生变化,从而使SATB2蛋白失去相应功能,导致疾病发生。结论本研究确定了该家系中先证者的致病突变位点为SATB2基因c.1165C>T(p.R389C),进一步丰富了中国人群中Glass综合征的基因突变谱及临床表型谱,为深入阐明该病的分子病理机制及临床诊疗提供参考数据。

Objective To identify the pathogenic gene variants in a family with Glass syndrome. Methods Clinical examination and whole exome sequencing were performed on the proband, the candidate mutation loci in the family members were evaluated by PCR-Sanger sequencing, the structure and function of the mutant protein were analyzed by I-TASSER software. Results The clinical manifestations of the proband were comprehensive developmental delay, including dental abnormalities, ataxia and failing to follow instructions. EEG examination indicated multifocal spikes, spikes and slow waves,multispindle spikes and slow waves, which is more pronounced during sleep period on the left side. The detected proband has a SATB2 gene(NM_015265) c.1165 C>T(p.R389 C) newborn heterozygous missense mutation, which was not detected in the parents.Protein structure and function prediction showed that p.R389 C missense mutation resulted in changing on the ligand domain, therefore loss function of the protein and causes disease. The phenotypic heterogeneity of Glass syndrome may be related to the difference of mutation sites and phenotypic penetrance in patients. Conclusion This study determined that the pathogenic mutation site of the proband in this family was SATB2 gene(NM_015265) c.1165 C>T(p.R389 C), which further enriches the gene mutation spectrum and clinical phenotype spectrum of Glass syndrome in the Chinese population, and provides reference data for in-depth elucidation of the molecular pathology of the disease and clinical diagnosis and treatment.