De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism
De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism
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DOI：
10.1007/s00439-017-1863-y
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发表时间：
2018-01-01
期刊：
影响因子：
5.3
通讯作者：
Saitsu, Hirotomo
中科院分区：
文献类型：
--
作者：
Hiraide, Takuya;Nakashima, Mitsuko;Saitsu, Hirotomo
SETD1B （SET domain containing 1B）是SET1组蛋白甲基转移酶复合物的一个组成部分，它介导组蛋白H3在赖氨酸4上的甲基化（H3K4）。在这里，我们描述了两个不相关的个体，通过三基全外显子组测序鉴定出SETD1B的新变体：c.5524C > T, p.（Arg1842Trp）和c.5575C > T, p.（Arg1859Cy）。这两种错义变异发生在进化上保守的氨基酸上，位于SET结构域，该结构域在催化组蛋白甲基化中起关键作用。先前的研究表明，包含SETD1B的12q24. 4.3区域的从头微缺失与发育迟缓、智力残疾、自闭症/自闭症行为、身材高大和颅面异常有关。对12q24.3缺失的比较定位细化了候选位点，表明KDM2B和SETD1B是12q24.3缺失综合征致病性最可信的候选基因。我们的病例表现为癫痫、发育迟缓、智力障碍、自闭症行为和颅面畸形特征，这些与从头缺失12q24.31的个体一致。因此，我们的研究提示SETD1B畸变可能是12q24.3缺失综合征的核心缺陷。
SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4). Here, we describe two unrelated individuals with de novo variants in SETD1B identified by trio-based whole exome sequencing: c.5524C > T, p.(Arg1842Trp) and c.5575C > T, p.(Arg1859Cy). The two missense variants occurred at evolutionarily conserved amino acids and are located within the SET domain, which plays a pivotal role in catalyzing histone methylation. Previous studies have suggested that de novo microdeletions in the 12q24.3 region encompassing SETD1B were associated with developmental delays, intellectual disabilities, autism/autistic behavior, large stature and craniofacial anomalies. Comparative mapping of 12q24.3 deletions refined the candidate locus, indicating KDM2B and SETD1B to be the most plausible candidate genes for the pathogenicity of 12q24.3 deletion syndrome. Our cases showed epilepsy, developmental delay, intellectual disabilities, autistic behavior and craniofacial dysmorphic features, which are consistent with those of individuals with de novo 12q24.31 deletions. Therefore, our study suggests that SETD1B aberration is likely to be the core defect in 12q24.3 deletion syndrome.