Folkhälsan Research Center, Helsinki 00290, Finland; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland.
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia; Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia.
Am J Hum Genet. 2021 Apr 1;108(4):722-738. doi: 10.1016/j.ajhg.2021.03.013.
Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.
进行性肌阵挛性癫痫（PMEs）是一组临床和遗传异质性罕见疾病。现在超过 70%的 PME 病例可以通过分子方法解决。已知的 PME 基因编码多种蛋白质，许多与溶酶体和内体功能有关。我们对 84 名（78 名无关联）未解决的受 PME 影响的个体进行了全外显子组测序（WES），这些个体有或没有额外的家庭成员，以发现新的病因。我们在 78 名无关联个体中的 24 名个体中发现了可能导致疾病的变异，尽管之前进行了基因分析。在作为三联体或家族进行研究的个体（14/28）中，诊断率明显高于作为单体进行研究的个体（10/50）（OR = 3.9，p 值 = 0.01，Fisher 精确检验）。24 例可能解决的 PME 病例涉及 18 个基因。首先，我们发现并功能验证了 NUS1 和 DHDDS 中的五个杂合变异和 ALG10 中的一个纯合变异，以前没有与疾病相关。这三个基因都参与了多萜醇依赖性蛋白糖基化，这一途径以前与 PME 无关。其次，我们独立验证了 SEMA6B 作为两个无关个体的显性 PME 基因。第三，在五个家庭中，我们在已建立的 PME 基因中发现了变异；三个与内含子或拷贝数变化有关（CLN6、GBA、NEU1），两个非常罕见的原因（ASAH1、CERS1）。第四，我们发现了一组通常与发育性和癫痫性脑病相关的基因，但在这里，令人惊讶的是，它们表现为 PME，无论是否存在先前的发育迟缓。我们对这些病例的系统分析表明，未解决病例的一小部分很可能是一系列非常罕见、遗传异质性的病因。
