Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, 7616914115, Iran.
Student Research Committee, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
Neurol Sci. 2021 Dec;42(12):5077-5085. doi: 10.1007/s10072-021-05196-0. Epub 2021 Mar 26.
Progressive myoclonic epilepsy-4 with or without renal failure (EPM4) is a rare neurological autosomal recessive disorder caused by mutations in SCARB2 gene. In this study, we described clinical features and genetic causes of an Iranian family with two affected individuals whose clinical manifestations closely resembled progressive myoclonus epilepsy.
Our proband was a 38-year-old male with a history of tremor, generalized seizures, action myoclonus, ataxia, and dysarthria that presumptive diagnosed as progressive myoclonus epilepsy. His older sister has the same symptoms. Whole-exome sequencing of DNA sample from the proband was performed. Candidate variant and cosegregation were confirmed by direct sequencing. Functional prediction of candidate variant was performed using appropriate prediction tools.
Genetic analysis identified a homozygous splicing c.423+1 G>A variant in the SCARB2 gene of the proband and his affected sister. Segregation study identified heterozygous state in four unaffected family members (parents and two children). The variant is localized at the first nucleotide of intron 3 and was not detected among in-house healthy controls. This variant was not reported in genetic databases and predicted to potentially alter the 5' donor splice site and disease causing using online prediction tools. It was classified as a likely pathogenic variant according to ACMG standards and guidelines.
This is the first report that demonstrates c.423+1 G>A variant in the SCARB2 gene segregating with the phenotype of EPM4 in a consanguineous Iranian family.
伴或不伴肾衰竭的进行性肌阵挛癫痫-4（EPM4）是一种罕见的常染色体隐性遗传性神经疾病，由 SCARB2 基因突变引起。在本研究中，我们描述了一个伊朗家系的临床特征和遗传病因，该家系中有两名受累个体，其临床表现与进行性肌阵挛癫痫非常相似。
我们的先证者是一名 38 岁男性，有震颤、全身性癫痫发作、动作性肌阵挛、共济失调和构音障碍病史，推测诊断为进行性肌阵挛癫痫。他的姐姐有相同的症状。对先证者的 DNA 样本进行全外显子组测序。通过直接测序确认候选变异和共分离。使用适当的预测工具对候选变异进行功能预测。
遗传分析在先证者及其受累姐姐的 SCARB2 基因中发现了一个纯合剪接 c.423+1 G>A 变异。在四个未受影响的家庭成员（父母和两个孩子）中发现了杂合状态。该变异位于内含子 3 的第一个核苷酸处，在内部健康对照中未检测到。该变异未在遗传数据库中报道，并通过在线预测工具预测可能改变 5'供体位点，导致疾病。根据 ACMG 标准和指南，将其归类为可能的致病性变异。
这是首例在一个近亲伊朗家系中，SCARB2 基因的 c.423+1 G>A 变异与 EPM4 的表型分离的报道。
