Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Department of Neurology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Department of Pediatrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, China.
Seizure. 2024 Mar;116:30-36. doi: 10.1016/j.seizure.2023.02.018. Epub 2023 Feb 27.
The MED12 gene 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. MED12 variants have previously been associated with developmental disorders with or without nonspecific intellectual disability. This study aims to explore the association between MED12 variants and epilepsy.
Trios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations of MED12 variants were analyzed.
Five hemizygous missense MED12 variants, 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.
MED12 is a potentially causative gene for X-linked recessive partial epilepsy without developmental or intellectual abnormalities. The genotype-phenotype correlation of MED12 variants explains the phenotypic variations and can help the genetic diagnosis.
MED12 基因编码中介体复合物亚基 12，是参与所有 RNA 聚合酶 II 依赖性基因转录调控的中介体复合物的一个组成部分。MED12 变体先前与伴有或不伴有非特异性智力障碍的发育障碍有关。本研究旨在探讨 MED12 变体与癫痫之间的关联。
对 349 例无获得性病因的部分（局灶性）癫痫无关三体型患者进行基于全外显子组测序。分析 MED12 变体的基因型-表型相关性。
在 5 名患有局灶性癫痫的男性无关患者中发现了 5 种半合子错义 MED12 变体，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。所有患者均表现为罕见的局灶性发作，且无发育异常或智力障碍而达到无癫痫发作。所有半合子变体均由无症状母亲遗传（符合 X 连锁隐性遗传模式），在一般人群中不存在。两种具有破坏性氢键的变体与早发性癫痫发作有关。进一步的基因型-表型分析表明，先天性异常疾病（Hardikar 综合征）与 X 连锁显性遗传模式中的（新生）破坏性变体有关，而癫痫与 X 连锁隐性遗传模式中的错义变体有关。智力障碍的表型特征在基因型和遗传方面均表现为中间表型。癫痫相关变体位于 MED12-LCEWAV 结构域和 MED12-LCEWAV 与 MED12-POL 之间的区域。
MED12 是一种潜在的导致 X 连锁隐性局灶性癫痫而无发育或智力异常的致病基因。MED12 变体的基因型-表型相关性解释了表型的变异，并有助于遗传诊断。
