Background: Progressive myoclonus epilepsies (PMEs) comprise a group of rare genetic disorders characterized by action myoclonus, epileptic seizures, and ataxia with progressive neurologic decline. Due to clinical and genetic heterogeneity of PMEs, it is difficult to decide which genes are affected. The aim of this study was to report an action myoclonus with or without renal failure syndrome (EPM4) family and summarize the clinical and genetic characteristics of all reported EPM4 patients.
Methods: In the present study, targeted next-generation sequencing (NGS) was applied to screen causative genes in a Chinese PME family. The candidate variant was further confirmed by cosegregation analysis and further functional analysis, including the reverse transcription polymerase chain reaction and Western blot of the proband's muscle. Moreover, literature data on the clinical and mutational features of all reported EPM4 patients were reviewed.
Results: The gene analysis revealed a novel homozygous splicing mutation (c.995-1G>A) of the SCARB2 gene in two brothers. Further functional analysis revealed that this mutation led to loss function of the SCARB2 protein. The classification of the candidate variant, according to the American College of Medical Genetics and Genomics standards and guidelines and functional analysis, was pathogenic. Therefore, these two brothers were finally diagnostically confirmed as EPM4.
Conclusions: These present results suggest the potential for targeted NGS to conduct a more rapid and precise diagnosis for PME patients. A literature review revealed that mutations in the different functional domains of SCARB2 appear to be associated with the phenotype of EPM4.
SCARB2基因新剪接位点纯合突变导致进行性肌阵挛癫痫伴或不伴肾功能衰竭摘要背景：进行性癫痫性肌阵挛（PMEs）是一组以肌阵挛、癫痫发作、共济失调及神经系统功能进行性减退为特点的罕见病。由于该病具有临床和基因异质性，明确疾病的致病基因有一定难度。 本文对一例EPM4家系进行了报道并总结了所有已报道EMP4患者的临床与基因突变特点。 方法：本研究应用目标区域测序在一个家系中检测 PMEs致病基因并对候选基因变异位点进行家系共分离分析以及对先证者肌肉细胞进行基因表达水平和蛋白表达水平分析。同时，回顾并总结所有已报道EPM4临床和突变特点的文献。 结果：通过基因分析发现，先证者及其兄长均携带SCARB2基因c.995-1G>A剪切位点突变。进一步实验发现该突变导致SCARB2蛋白功能缺失。根据美国医学遗传学和基因组学学院(ACMG)标准和指南，该候选变异位点为致病突变，该兄弟最终被确诊EPM4。 结论：靶向二代测序未来有望成为更加快速精准诊断PMEs的方法。通过回顾相关文献表明EPM4的表型与突变位点所在SCARB2基因功能域有关。.
Keywords: Gene; Progressive Myoclonus Epilepsies; Progressive Myoclonus Epilepsy with or without Renal Failure; SCARB2; Targeted Next-Generation Sequencing.