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 pro-tein stability in vivo.Additionally,p.A438T disrupts the interaction of RBM42 with hnRNP K,which is the causa-tive 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△FgRbp1 in Fusarium while it was rescued by the wild-type(WT)human RBM42.A mouse model carying Rbm42 compound heterozygous variants,c.280C>T(p.Q94*)and c.1306_1308delinsACA(p.A436T),demonstrated gross fetal develop-mental 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.

Integrated facial analysis and targeted sequencing identifies a novel KDM6A pathogenic variant resulting in Kabuki syndrome

Kabuki syndrome(KS)is a rare congenital mental retardation condition characterized by facial dysmorphia,visceral and skeletal malformations,and developmental delay.The integrated phenotype and genotype-based prioritization is critical for diagnoses of genetic diseases.In this study,a Chinese woman,presenting with characteristic facial features of KS,came for pre-pregnancy consultation.We aimed to clarify the diagnosis and provide pre-pregnancy genetic counseling.Facial dysmorphology analysis and next-generation sequencing-based multigene panel approach were used to identify candidate syndromes and causative variants,respectively.The candidate variant was verified by Sanger sequencing.We identified a novel de novo KDM6A pathogenic variant(c.3521G>A)in the woman,which was in line with the Face2Gene analysis result.Peripheral blood RNA assay showed that the variant transcript underwent the nonsense-mediated mRNA decay and led to subsequent haploinsufficiency of KDM6A.Our study provides the genetic diagnosis method for KS type 2 and identifies the first KDM6A point variant in Chinese patient.

A novel preimplantation genetic testing strategy for a subtelomeric genetic disorder:A case study

Preimplantation genetic testing(PGT)is a precise and effective technique for detecting inherited pathogenic mutations to prevent birth defects.However,there are few reports on PGT for pseudo-autosomal genetic diseases.