低镁血症、癫痫和智力障碍综合征患儿1例的CNNM2基因变异分析

Analysis of CNNM2 gene variant in a child with Hypomagnesemia,seizures,and mental retardation syndrome

目的探讨1例儿童低镁血症、癫痫和智力障碍(HSMR)综合征患者的分子遗传学病因。方法选取2021年7月9日因"反复抽搐2个月"收治于山东大学附属儿童医院的HSMR综合征患儿作为研究对象,并收集其临床资料。采集患儿及父母的外周血样,提取基因组DNA,应用全外显子组测序技术进行基因检测,确定候选变异位点,Sanger测序家系验证。应用生物信息学分析软件SWISS-MODEL对蛋白质结构模型进行预测。结果患儿为男性,就诊时为1岁7月龄,临床表现为癫痫发作、全面性发育迟缓,血清学检测提示低血清镁。基因检测结果提示患儿CNNM2基因存在c.1448delT(p.Val483GlyfsTer29)杂合变异,考虑为新发变异。该变异使CNNM2基因第1448位核苷酸T发生缺失,导致第483位氨基酸由缬氨酸变成甘氨酸,且下游第29位氨基酸变为终止密码子。SWISS-MODEL软件分析提示该变异位点导致蛋白结构发生改变,产生截短蛋白。根据美国医学遗传学与基因组学学会遗传变异与分类指南,c.1448del T(p.Val483GlyfsTer29)评级为致病性变异(PVS1+PS2+PM2Supporting+PP4)。结论CNNM2基因c.1448delT杂合变异考虑为HSMR综合征患儿的致病原因,该变异的发现丰富了CNNM2基因表型-基因型。

Objective To explore the genetic etiology of a child with Hypomagnesemia,epilepsy and mental retardation syndrome(HSMR).Methods A child who was admitted to the Children′s Hospital of Shandong University on July 9,2021 due to repeated convulsions for 2 months was selected as the study subject.Clinical data of the child was collected.Peripheral blood samples of the child and his pedigree members were collected for the extraction of genomic DNA.Whole exome sequencing was carried out,and candidate variant was verified by Sanger sequencing and bioinformatic analysis.Results The child,a 1-year-and-7-month-old male,had presented with epilepsy and global developmental delay.Serological testing revealed that he has low serum magnesium.Genetic testing showed that the child has harbored a heterozygous c.1448delT(p.Val483GlyfsTer29)variant of the CNNM2 gene,which was de novo in origin.The variant has caused substitution of the valine at position 483 to Glycine and formation of a termination codon after 29 amino acids at downstream.As predicted by Swiss-Model online software,the variant may alter the protein structure,resulting in a truncation.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.1448del T(p.Val483GlyfsTer29)was predicted as a pathogenic variant(PVS1+PS2+PM2_Supporting+PP4).Conclusion The heterozygous c.1448delT variant of the CNNM2 gene probably underlay the HSMR in this child.Above finding has enriched the phenotype-genotype specirum of the CNNM2 gene.