Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with bi-allelic loss-of-function variants in the RBM42 gene. The patient is a two-year-old female with severe central nervous system abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing. Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global alternative splicing to abnormal embryonic development.

中文翻译：

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RBM42 中的双等位基因变异导致涉及神经、面部、心脏和肌肉骨骼的多系统疾病。

在这里，我们报告了一种以前未被识别的综合征性神经发育障碍，与 RBM42 基因中的双等位基因功能丧失变异相关。患者是一名两岁的女性，患有严重的中枢神经系统异常、肌张力减退、听力下降、先天性心脏缺陷和面部特征畸形。家族性全外显子组测序显示，该患者在编码剪接复合物的一个组成部分的 RBM42 基因中有两个复合杂合变异，c.304C>T (p.R102*) 和 c.1312G>A (p.A438T)在 RNA 结合基序蛋白家族中。p.A438T 变体位于 RRM 域中，这会损害 RBM42 蛋白在体内的稳定性。此外，p.A438T 破坏了 RBM42 与 hnRNP K 的相互作用，hnRNP K 是 Au-Kline 综合征的致病基因，在指示患者中观察到具有重叠的疾病特征。人 R102* 或 A438T 突变蛋白未能完全挽救镰刀菌中 RBM42 直系同源敲除 ΔFgRbp1 的生长缺陷，而野生型人 RBM42 挽救了它。携带 Rbm42 复合杂合变体 c.280C>T (p.Q94*) 和 c.1306_1308delinsACA (p.A436T) 的小鼠模型表现出严重的胎儿发育缺陷，大多数双突变动物死于 E13.5。RNA-seq 数据证实 Rbm42 参与神经和心肌功能，并在可变剪接中发挥重要作用。总的来说，我们提供临床、遗传和功能数据来证明 RBM42 中的缺陷构成了一种新的神经发育疾病的潜在病因，这种疾病将全局可变剪接的失调与胚胎发育异常联系起来。