Purpose

MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes.

Methods

By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12.

Results

Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants.

Conclusion

We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

中文翻译：

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MED12 的从头变异导致 18 名女性出现 X 连锁综合征神经发育障碍

目的

MED12 是介体多蛋白复合物的一个亚基，在 RNA 聚合酶 II 转录和细胞生长、发育和分化的调节中起核心作用。这可能是MED12中携带错义变异的男性可变表型的基础，包括 X 连锁隐性 Ohdo、Lujan 和 FG 综合征。

方法

通过国际配对，我们收集了 18 名女性的变异和临床数据，这些女性患有多变的神经发育障碍 (NDD)，并在MED12中含有从头变异。

结果

五个无义变体聚集在 C 末端区域，两个剪接变体在同一个外显子 8 剪接受体位点发现，11 个错义变体分布在基因/蛋白质上。蛋白质截短变异与严重的综合征表型相关，包括智力障碍 (ID)、面部畸形、身材矮小、骨骼异常、喂养困难和可变的其他异常。从头错义变异与特异性较低但同质的表型相关，包括严重的 ID、自闭症特征、言语受限和可变的其他异常，与具有截断变异的女性和具有错义变异的男性重叠。

结论

我们将MED12中的从头截断变体确定为导致不同 NDD 的原因，并将从头错义变体确定为女性中严重、特异性较低的 NDD 的原因。