Clinical and genetic analysis of a child with Cerebral creatine deficiency syndrome due to variant ofSLC6A8 gene
张赟健 1丁一峰 1李奕洁 1周水珍 1许芯
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作者信息
1. 复旦大学附属儿科医院神经科，上海 201102
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摘要
目的 探讨1例由SLC6A8基因变异所致脑肌酸缺乏综合征(CCDS)患儿的临床表现及遗传学特点。 方法 选取2021年3月5日因"间断抽搐发作1月余"就诊于复旦大学附属儿科医院的1例CCDS患儿作为研究对象，收集其临床资料。应用全外显子组测序(WES)对患儿进行基因变异分析，对可能的变异位点通过Sanger测序进行验证并应用转录组测序(RNA-seq)技术验证剪接变异。 结果 患儿为1岁10月龄男性，精神运动发育落后，1岁9月龄始无热惊厥发作，母亲与外婆均有惊厥发作史，患儿头颅MRS示双侧基底节区及丘脑肌酸峰降低，提示脑肌酸缺乏。WES结果发现患儿X染色体SLC6A8基因存在c.1767+1_1767+2insA剪接变异，母亲及外婆均为该变异杂合子。RNA-seq结果显示患儿SLC6A8基因exon12处存在异常可变剪接事件，该变异导致蛋白发生截短。根据美国医学遗传学与基因组学学会变异指南，c.1767+1_1767+2insA评级为可能致病变异(PVS1_Strong+PM2_Supporting+PP4)。 结论 SLC6A8基因c.1767+1_1767+2insA变异考虑是该CCDS患儿致病原因。该变异的检出丰富了该基因的变异谱。 Objective To explore the clinical features and genetic variant in a child with Cerebral creatine deficiency syndrome (CCDS). Methods A child who had presented at the Affiliated Children′s Hospital of Fudan University on March 5, 2021 was selected as the study subject. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing. The level of creatine in the brain was determined by magnetic resonance spectroscopy. Results The patient, a 1-year-and-10-month male, had presented with developmental delay and epilepsy. Both his mother and grandmother had a history of convulsions. MRS showed reduced cerebral creatine in bilateral basal ganglia and thalamus. The child was found to harbor a hemizygous splicing variant of the SLC6A8 gene, namely c. 1767+ 1_1767+ 2insA, which may lead to protein truncation. The variant was not found in the public databases. Both his mother and grandmother were heterozygous carriers for the same variant. Conclusion The hemizygous c. 1767+ 1_1767+ 2insA variant of the SLC6A8 gene probably underlay the CCDS in this child. Discovery of the novel variant has also expanded the mutational spectrum of the SLC6A8 gene.
Abstract
Objective To explore the clinical features and genetic variant in a child with Cerebral creatine deficiency syndrome (CCDS). Methods A child who had presented at the Affiliated Children′s Hospital of Fudan University on March 5, 2021 was selected as the study subject. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing. The level of creatine in the brain was determined by magnetic resonance spectroscopy. Results The patient, a 1-year-and-10-month male, had presented with developmental delay and epilepsy. Both his mother and grandmother had a history of convulsions. MRS showed reduced cerebral creatine in bilateral basal ganglia and thalamus. The child was found to harbor a hemizygous splicing variant of the SLC6A8 gene, namely c. 1767+ 1_1767+ 2insA, which may lead to protein truncation. The variant was not found in the public databases. Both his mother and grandmother were heterozygous carriers for the same variant. Conclusion The hemizygous c. 1767+ 1_1767+ 2insA variant of the SLC6A8 gene probably underlay the CCDS in this child. Discovery of the novel variant has also expanded the mutational spectrum of the SLC6A8 gene.
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