Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes
Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes
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DOI：
10.1001/jamaneurol.2017.1714
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发表时间：
2017-10-01
期刊：
影响因子：
29
通讯作者：
Koeleman, Bobby P. C.
中科院分区：
文献类型：
--
作者：
de Kovel, Carolien G. F.;Syrbe, Steffen;Koeleman, Bobby P. C.
了解KCNB1错义或功能丧失变异患者的症状范围，以及这些症状与变异类型的相关性，将有助于临床医生在治疗新患者时进行诊断和预后。目的研究与KCNB1变异相关的临床谱和基因型-表型相关性。设计、环境和参与者本研究总结了KCNB1推定致病性变异患者的临床和遗传信息。患者是在研究项目或临床试验中确定的。从以前发表的文章中收集患者信息，并在可行的情况下联系作者。所有患者都在其中一个参与研究所的诊所就诊，因为他们可能患有遗传疾病。他们要么在临床环境中接受测试，要么被纳入研究项目。主要结果和测量方法基因变异及其遗传以及患者症状和特征的信息以预定义的格式呈现。所有变异均通过大量平行测序鉴定，并通过Sanger测序在患者中得到证实。除一个家庭外，所有家庭的Sanger测序均证实父母中没有该变异。结果26例发育迟缓患者（女性10例，男性15例，未知1例，入组时平均年龄9.8岁，年龄范围2 ~ 32岁）中，20例（77%）携带KCNB1离子通道区域错义变异，变异集中在S5 ~ S6区。导致过早停止的三个变体位于c端，3个位于离子通道域。25例患者中有21例（84%）有癫痫发作，其中9例（36%）在3至18个月大之间开始癫痫性痉挛。所有患者均出现发育迟缓，其中17例（65%）出现严重发育迟缓；14例（82%）严重迟缓患者有行为问题。6例停止变异体患者中有4例发育迟缓较轻，1例S2跨膜元件变异体而不是S4至S6区变异体。结论和相关性离子通道区域的新发KCNB1错义变异以及该区域和c末端的功能缺失变异可能导致伴有或不伴有癫痫发作的神经发育障碍。假定具有KCNB1致病变异的患者具有可变的表型。然而，蛋白质变异的类型和位置与疾病的严重程度（不完全）相关。
IMPORTANCE Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients.OBJECTIVES To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations.DESIGN, SETTING, AND PARTICIPANTS This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project.MAIN OUTCOMES AND MEASURES The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one.RESULTS Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region.CONCLUSIONS AND RELEVANCE De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.