PDF(Pubmed)
Abstract：
BACKGROUND: Primary periodic paralysis (PPP) is an inherited disorders of ion channel dysfunction characterized by recurrent episodes of flaccid muscle weakness, which can classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. However, PPP is charactered by remarkable clinical and genetic heterogeneity, and the diagnosis of suspected patients is based on the characteristic clinical presentation then confirmed by genetic testing. At present, there are only limited cohort studies on PPP in the Chinese population.
RESULTS: We included 37 patients with a clinical diagnosis of PPP. Eleven (29.7%) patients were tested using a specific gene panel and 26 (70.3%) by the whole-exome sequencing (WES). Twenty-two cases had a genetic variant identified, representing a diagnostic rate of 59.5% (22/37). All the identified mutations were either in the SCN4A or the CACNA1S gene. The overall detection rate was comparable between the panel (54.5%: 6/11) and WES (61.5%: 16/26). The remaining patients unresolved through panel sequencing were further analyzed by WES, without the detection of any mutation. The novel atypical splicing variant c.2020-5G > A affects the normal splicing of the SCN4A mRNA, which was confirmed by minigene splicing assay. Among 21 patients with HypoPP, 15 patients were classified as HypoPP-2 with SCN4A variants, and 6 HypoPP-1 patients had CACNA1S variants.
CONCLUSIONS: Our results suggest that SCN4A alleles are the main cause in our cohort, with the remainder caused by CACNA1S alleles, which are the predominant cause in Europe and the United States. Additionally, this study identified 3 novel SCN4A and 2 novel CACNA1S variants, broadening the mutation spectrum of genes associated with PPP.
RESULTS: We included 37 patients with a clinical diagnosis of PPP. Eleven (29.7%) patients were tested using a specific gene panel and 26 (70.3%) by the whole-exome sequencing (WES). Twenty-two cases had a genetic variant identified, representing a diagnostic rate of 59.5% (22/37). All the identified mutations were either in the SCN4A or the CACNA1S gene. The overall detection rate was comparable between the panel (54.5%: 6/11) and WES (61.5%: 16/26). The remaining patients unresolved through panel sequencing were further analyzed by WES, without the detection of any mutation. The novel atypical splicing variant c.2020-5G > A affects the normal splicing of the SCN4A mRNA, which was confirmed by minigene splicing assay. Among 21 patients with HypoPP, 15 patients were classified as HypoPP-2 with SCN4A variants, and 6 HypoPP-1 patients had CACNA1S variants.
CONCLUSIONS: Our results suggest that SCN4A alleles are the main cause in our cohort, with the remainder caused by CACNA1S alleles, which are the predominant cause in Europe and the United States. Additionally, this study identified 3 novel SCN4A and 2 novel CACNA1S variants, broadening the mutation spectrum of genes associated with PPP.
摘要：
背景：原发性周期性麻痹（PPP）是一种遗传性离子通道功能障碍，其特征是反复发作的弛缓性肌肉无力，可以归类为低钾血症(HypoPP)，normokalemic（NormoPP），根据麻痹性发作期间的钾水平或高钾血症（HyperPP）。然而,PPP具有显著的临床和遗传异质性,可疑患者的诊断是基于特征临床表现，然后通过基因检测证实。目前,在中国人群中，关于PPP的队列研究有限。
结果：我们纳入了37例临床诊断为PPP的患者。11名（29.7%）患者使用特定基因组进行了测试，26名（70.3%）患者通过全外显子组测序（WES）进行了测试。22例病例发现了遗传变异，诊断率为59.5%(22/37)。所有鉴定的突变都在SCN4A或CACNA1S基因中。总体检出率在面板（54.5％：6/11）和WES（61.5％：16/26）之间相当。通过WES进一步分析了通过小组测序未解决的其余患者，没有检测到任何突变。新型非典型剪接变体c.2020-5G>A影响SCN4AmRNA的正常剪接，通过小基因剪接试验证实。在21例HypoPP患者中，15例患者被分类为具有SCN4A变体的HypoPP-2，6例HypoPP-1患者有CACNA1S变异。
结论：我们的结果表明，SCN4A等位基因是我们队列中的主要原因，其余的由CACNA1S等位基因引起，这是欧洲和美国的主要原因。此外,这项研究鉴定了3个新的SCN4A和2个新的CACNA1S变体，拓宽与PPP相关基因的突变谱。
结果：我们纳入了37例临床诊断为PPP的患者。11名（29.7%）患者使用特定基因组进行了测试，26名（70.3%）患者通过全外显子组测序（WES）进行了测试。22例病例发现了遗传变异，诊断率为59.5%(22/37)。所有鉴定的突变都在SCN4A或CACNA1S基因中。总体检出率在面板（54.5％：6/11）和WES（61.5％：16/26）之间相当。通过WES进一步分析了通过小组测序未解决的其余患者，没有检测到任何突变。新型非典型剪接变体c.2020-5G>A影响SCN4AmRNA的正常剪接，通过小基因剪接试验证实。在21例HypoPP患者中，15例患者被分类为具有SCN4A变体的HypoPP-2，6例HypoPP-1患者有CACNA1S变异。
结论：我们的结果表明，SCN4A等位基因是我们队列中的主要原因，其余的由CACNA1S等位基因引起，这是欧洲和美国的主要原因。此外,这项研究鉴定了3个新的SCN4A和2个新的CACNA1S变体，拓宽与PPP相关基因的突变谱。
