背景:几种基因的致病变异与分离或联合肌张力障碍的遗传形式有关。这些基因的表型和遗传谱以及致病变异的频率尚未完全阐明,无论是肌张力障碍患者还是其他患者,有时并发运动障碍,如帕金森病(PD)。
目的:筛选>2000例肌张力障碍或PD患者中已知的肌张力障碍致病基因的罕见变异。
方法:我们筛选了1207名来自德国的肌张力障碍患者(DysTract联盟),西班牙,还有韩国,和1036名来自德国的PD患者使用下一代测序基因小组进行致病性变异。通过分析基因的特征性表观标记来评估对KMT2B变异体DNA甲基化的影响。
结果:我们确定了131个罕见变异(次要等位基因频率<0.005)的171个携带者(109个患有肌张力障碍[9.0%];62个患有PD[6.0%])。共有52例患者(48个肌张力障碍[4.0%];4个PD[0.4%,全部具有GCH1变体])携带33种不同的(可能的)致病性变体,其中17个以前没有报道过。PRKRA中未发现致病性双等位基因变异。48个KMT2B变体的表观标记分析显示,其中只有两个应该被认为是(可能的)致病性。
结论:这项研究证实了GCH1,GNAL,KMT2B,SGCE,THAP1和TOR1A是肌张力障碍的相关原因,并扩展了突变谱。值得注意的是,在PD患者中也发现仅GCH1可能的致病变异.对于DYT-KMT2B,最近描述的表观特征可作为确定新鉴定的变异体的功能效应的可靠读数.©2024作者由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson\'s disease (PD).
OBJECTIVE: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes.
METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of
KMT2B variants was evaluated by analyzing the gene\'s characteristic episignature.
RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48
KMT2B variants revealed that only two of these should be considered (likely) pathogenic.
CONCLUSIONS: This study confirms pathogenic variants in GCH1, GNAL,
KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-
KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.