Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study
Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study
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DOI：
10.1016/s1474-4422(12)70182-5
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发表时间：
2012-09-01
期刊：
影响因子：
48
通讯作者：
Gaertner, Jutta
中科院分区：
文献类型：
--
作者：
Rosewich, Hendrik;Thiele, Holger;Gaertner, Jutta
背景 儿童交替性偏瘫（AHC）是一种罕见的神经系统疾病，其特征是早发性偏瘫、肌张力障碍、各种阵发性症状和发育障碍。几乎所有 AHC 病例都是散发的，但单卵双胞胎中的 AHC 一致性以及表型较温和的家庭中的显性传播已有报道。因此，我们的目的是确定与这种疾病相关的从头突变。方法我们从2004年9月至2012年5月18日期间，在父母支持小组的帮助下，从德国儿科神经科招募了具有临床特征的AHC患者。我们使用三名先证者父母三人组的全外显子组测序来鉴定与疾病相关的基因，然后测试该基因的突变是否也存在于其余患者及其患者中。 健康的父母。我们分析了基因型并描述了它们与疾病表型谱的关联。结果我们研究了 15 名女性和 9 名男性 AHC 患者，年龄为 8-35 岁。 ATP1A3 作为 AHC 中的疾病相关基因出现。全外显子组测序显示三个杂合的从头错义突变。对其余 21 名受影响个体的测序发现，所有患者的 ATP1A3 均与疾病相关，其中包括 6 种从头错义突变和 1 种从头剪接位点突变。由于 ATP1A3 也是与快速发作性肌张力障碍-帕金森症相关的基因（DYT12，OMIM 128235），因此我们将队列中 AHC 患者的基因型和表型与科学文献中报道的快速发作性肌张力障碍-帕金森症患者的基因型和表型进行了比较。我们注意到重叠的临床特征，例如经常由情绪压力引发的肌张力障碍突然发作、累及的头尾（从脸到手臂到腿）梯度和脑干功能障碍的体征，以及明显区分的临床特征，例如阵发性偏瘫和四肢瘫痪。 解释 符合临床标准的患者中 ATP1A3 基因的突变分析 AHC 可以进行明确的基因诊断和健全的遗传咨询。 AHC 和快速发作的肌张力障碍-帕金森病是与 ATP1A3 突变相关的等位基因疾病，并形成肌张力障碍运动障碍的表型连续体。
Background Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease.Methods We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease.Findings We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia.Interpretation Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder.