Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum
Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum
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DOI：
10.1111/cge.13067
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发表时间：
2018-02
影响因子：
3.5
通讯作者：
Michiko Yoshida;M. Nakashima;Tohru Okanishi;Sotaro Kanai;A. Fujimoto;Kazuya Itomi;M. Morimoto;H. Saitsu;Mitsuhiro Kato;Naomichi Matsumoto;T. Chiyonobu
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作者：
Michiko Yoshida;M. Nakashima;Tohru Okanishi;Sotaro Kanai;A. Fujimoto;Kazuya Itomi;M. Morimoto;H. Saitsu;Mitsuhiro Kato;Naomichi Matsumoto;T. Chiyonobu
BCL 11 A编码在造血组织和脑中高度表达的锌指蛋白，并且已知其作为胎儿血红蛋白（HbF）的转录抑制物起作用。最近，BCL 11 A的新生变异体在患有智力残疾综合征而无癫痫的个体中有报道。在这项研究中，我们对302例癫痫性脑病（EE）患者进行了全外显子组测序，并鉴定了2种新的BCL 11 A变体，c.577delC（p.His193Metfs*3）和c.2351A>C（p.Lys784Thr）。这两名患者都具有BCL 11 A相关智力残疾综合征的主要身体特征，这表明特征性身体特征和HbF的持续性应使临床医生怀疑由BCL 11 A致病性变异引起的EE。具有移码变体的患者1表现为伦诺克斯-加斯托综合征，其扩大了BCL 11 A单倍不足的表型谱。患者2，p.Lys784Thr变异，出现West综合征，随后出现耐药性局灶性癫痫发作和更严重的发育障碍。这2例新描述的患者有助于描述BCL 11 A致病变体的相关但不确定的表型特征。
BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole‐exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified 2 novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both the patients shared major physical features characteristic of BCL11A‐related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox‐Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug‐resistant focal seizures and more severe developmental disability. These 2 newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease‐causing variants.