Zech Michael, Jech Robert, Havránková Petra, Fečíková Anna, Berutti Riccardo, Urgošík Dušan, Kemlink David, Strom Tim M, Roth Jan, Růžička Evžen, Winkelmann Juliane
Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.
Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Mov Disord. 2017 Jul;32(7):1087-1091. doi: 10.1002/mds.27026. Epub 2017 May 18.
Recently a novel syndrome of childhood-onset generalized dystonia originating from mutations in lysine-specific methyltransferase 2B (KMT2B) has been reported.
We sequenced the exomes of 4 generalized dystonia-affected probands recruited from a Prague movement disorders center (Czech Republic). Bioinformatics analyses were conducted to select candidate causal variants in described dystonia-mutated genes. After cosegregation testing, checklists from the American College of Medical Genetics and Genomics were adopted to judge variant pathogenicity.
Three novel, predicted protein-damaging missense variants in KMT2B were identified (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln). Meeting pathogenicity criteria, p.Glu1234Lys was absent from population-based controls, situated in a key protein domain, and had occurred de novo. The associated phenotype comprised adolescence-onset generalized isolated dystonia with prominent speech impairment. Although linked to a similar clinical expression, p.Ala1541Val and p.Arg1779Gln remained of uncertain significance.
Rare missense variation in KMT2B represents an additional cause of generalized dystonia. Application of sequence interpretation standards is required before assigning pathogenicity to a KMT2B missense variant. © 2017 International Parkinson and Movement Disorder Society.
最近有报道称，一种由赖氨酸特异性甲基转移酶2B（KMT2B）突变引起的儿童期起病的全身性肌张力障碍新综合征。
我们对从布拉格运动障碍中心（捷克共和国）招募的4名全身性肌张力障碍先证者的外显子组进行了测序。进行生物信息学分析以选择已描述的肌张力障碍突变基因中的候选致病变异。在共分离测试后，采用美国医学遗传学与基因组学学会的清单来判断变异的致病性。
在KMT2B中鉴定出三个新的、预测会破坏蛋白质的错义变异（p.Glu1234Lys、p.Ala1541Val、p.Arg1779Gln）。p.Glu1234Lys符合致病性标准，在基于人群的对照中不存在，位于关键蛋白质结构域，且为新发突变。相关表型包括青春期起病的全身性孤立性肌张力障碍并伴有明显的言语障碍。虽然与类似的临床表型相关，但p.Ala1541Val和p.Arg1779Gln的意义仍不确定。
KMT2B中罕见的错义变异是全身性肌张力障碍的另一个病因。在将致病性归因于KMT2B错义变异之前，需要应用序列解释标准。©2017国际帕金森病和运动障碍协会。
