MED12 variants associated with X-linked recessive partial epilepsy without intellectual disability
MED12 variants associated with X-linked recessive partial epilepsy without intellectual disability
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DOI：
10.1016/j.seizure.2023.02.018
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发表时间：
2024-04-05
影响因子：
3
通讯作者：
Qiao，Jiang-Da
中科院分区：
文献类型：
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作者：
Yang，Jie-Hua;Liu，Zhi-Gang;Qiao，Jiang-Da
MED 12基因编码介体复合物亚基12，是介体复合物的一个组成部分，参与几乎所有RNA聚合酶II依赖基因的转录调控，MED 12变异体与发育障碍伴或不伴非特异性智力残疾有关。本研究旨在探讨MED 12变异体与epilepsy.Materials and MethodsTrios为基础的全外显子组测序进行了一个队列的349例无关的部分（局灶性）癫痫无后天原因。结果在5例无血缘关系的男性部分性癫痫患者中发现了5种半合子错义突变，包括c.958A>G/p.Ile320Val、c.1757G>A/p.Ser586Asn、c.2138C>T/p.Pro713Leu、c.3379T>C/p.Ser1127Pro和c.4219A>C/p.Met1407Leu。所有患者均表现出罕见的局灶性癫痫发作，并实现了无癫痫发作，无发育异常或智力残疾。所有的半合子变异体都遗传自无症状的母亲（与X连锁隐性遗传模式一致），并且在一般人群中不存在。这两种具有破坏性氢键的变异体与早发性癫痫发作有关。进一步的基因型-表型分析显示，先天性异常疾病（Hardikar综合征）与X连锁显性遗传模式中的（从头）破坏性变异相关，而癫痫与X连锁隐性遗传模式中的错义变异相关。智力残疾的表型特征在基因型和遗传方面均表现为中间表型。在MED 12-LCEWAV结构域和MED 12-POL之间的区域存在癫痫相关变异。结论MED 12是X连锁隐性部分性癫痫的潜在致病基因。MED 12变异体的基因型-表型相关性解释了表型变异，有助于基因诊断。
ObjectivesTheMED12gene encodes mediator complex subunit 12, which is a component of the mediator complex involved in the transcriptional regulation of nearly all RNA polymerase II-dependent genes.MED12variants have previously been associated with developmental disorders with or without nonspecific intellectual disability. This study aims to explore the association betweenMED12variants and epilepsy.Materials and methodsTrios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations ofMED12variants were analyzed.ResultsFive hemizygous missenseMED12variants, including c.958A>G/p.Ile320Val, c.1757G>A/p.Ser586Asn, c.2138C>T/p.Pro713Leu, c.3379T>C/p.Ser1127Pro, and c.4219A>C/p.Met1407Leu were identified in five unrelated males with partial epilepsy. All patients showed infrequent focal seizures and achieved seizure free without developmental abnormalities or intellectual disability. All the hemizygous variants were inherited from asymptomatic mothers (consistent with the X-linked recessive inheritance pattern) and were absent in the general population. The two variants with damaging hydrogen bonds were associated with early-onset seizures. Further genotype-phenotype analysis revealed that congenital anomaly disorder (Hardikar syndrome) was associated with (de novo) destructive variants in an X-linked dominant inheritance pattern, whereas epilepsy was associated with missense variants in an X-linked recessive inheritance pattern. Phenotypic features of intellectual disability appeared as the intermediate phenotype in terms of both genotype and inheritance. Epilepsy-related variants were located at the MED12-LCEWAV domain and the regions between MED12-LCEWAV and MED12-POL.ConclusionMED12is a potentially causative gene for X-linked recessive partial epilepsy without developmental or intellectual abnormalities. The genotype-phenotype correlation ofMED12variants explains the phenotypic variations and can help the genetic diagnosis.