Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) 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 (WT) 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 (AS). 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 AS to abnormal embryonic development.

The research of causative genes and phenotypic features in Chinese families with thoracic aortic aneurysm and dissec-tion / 中华胸心血管外科杂志

Objective This study aimed at exploring the causative genes and summarizing the clinical characteristics in two Chinese families with thoracic aortic aneurysm and dissection ( TAAD ) .Methods The whole exome capture and high throughput sequencing were applied to identify the causative gene.Family members were examined for features of syndromic ge-netic diseases by clinician and geneticist.Results Four known TAAD candidate genes were identified in family TAA01:rs140598(FBN1), rs185661462(MYH11), rs77620762(MYLK3), and rs111426349(TGFBR1).The TGFBR1 mutation (c.1459C>T) had been confirmed to co-segregate with the TAAD phenotype in all affected family members.Early onset of aortic root dilatation was significant in this family , and the average age at diagnosis of aortic root dilatation or aneurysm was23. 2 years.ACTA2(c.445C>T) was proved in family TAA02, and livedo reticularis was confirmed.Conclusion The causa-tive genes were identified via whole exome capture and high throughput sequencing in two TAAD families .Early onset of aortic root aneurysm was proved in TAA01, while livedo reticularis was found in TAA02.

Effects of Trihexyphenidyl on Monoamine Neurotransmitters in Cerebral Cortex after Subarachnoid Hemorrhage / 复旦学报（医学版）

Purpose　To study the effects of trihexyphenidyl (THP) on levels of monoamine neurotransmitters in the cerebral cortex after subarachnoid hemorrhage (SAH).　Methods　SAH model of rats were used,the levels of norepinephrine (NE),dopamine(DA),5-hydroxytrypatamine (5?HT) and hydroxyindoleacetic acid (5?HIAA) were measured by flurospectrophotometry.　Results　There was an extensive increase in levels of NE (P<0.01),5?HT (P<0.01) and 5?HIAA (P<0.01) in the cerebral cortex after SAH,DA had a tendency to increase without significance.The increase in levels of NE (P<0.01),5?HT (P<0.01) and 5?HIAA (P<0.05) in the cerebral cortex after SAH could be effectively inhibited by THP.　Conclusions　There will be a remarkable increase in levels of NE,5HT and 5HIAA in the cerebral cortex after SAH,THP could significantly ameliorate the metabolic disorder of NE and 5HT after SAH