Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy
Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy
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ACTL6B编码神经元特异性染色质重塑复合物nBAF的一个亚基，其突变会导致伴有脑白质减少和小脑萎缩的早发性严重发育性和癫痫性脑病。
DOI：
10.1007/s00439-019-01972-3
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发表时间：
2019-02-01
期刊：
影响因子：
5.3
通讯作者：
Elia, Maurizio
中科院分区：
文献类型：
--
作者：
Fichera, Marco;Failla, Pinella;Elia, Maurizio
发育性和癫痫性脑病（DEE）是遗传异质性疾病，通常以早发、EEG发作间期癫痫样异常、多形性和耐药性癫痫发作以及神经发育障碍为特征。在这项研究中，我们调查了两个兄弟姐妹的遗传缺陷，他们表现为严重的DEE，小头畸形，痉挛性四肢瘫痪，弥漫性脑髓鞘形成不足，小脑萎缩，身材矮小和脊柱后凸。全外显子组下一代测序（WES）在两个兄弟姐妹中鉴定出ACTL 6 B基因（NM_016188：c.820C>T;p.Gln274*）的纯合无义变体，编码神经元特异性染色质重塑复合物nBAF的亚基。为了进一步支持这些发现，对85个不相关的DEE个体的群组进行靶向ACTL 6 B测序测定，导致在患者中鉴定纯合错义变体（NM_016188：c.1045G>A;p.Gly349Ser）。该变异在该家系未受影响的同胞中没有分离，并且被几种预测软件归类为有害的。有趣的是，在这两个家庭中，纯合子患者共享一个相当同质的表型。在神经发育障碍和/或先天性脑畸形患者的WES队列研究中，很少有ACTL 6 B基因变异的患者零星报告。然而，文献中报告的临床信息不完整的患者数量有限，无法建立强有力的基因-疾病关联。在这里，我们提供了三个新的情况下，支持ACTL 6 B基因突变在DEE综合征形式的致病作用的额外的遗传和临床数据。
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.