[Clinical and genetic analysis of a Chinese pedigree affected with MRXS34 syndrome due to variant of NONO gene].

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OBJECTIVE: To explore the clinical phenotypes and genetic etiology of a child with MRXS34 syndrome due to a variant of NONO gene. METHODS: A child patient who presented at Shanxi Provincial Maternity and Child Care Hospital on September 28, 2020 was selected as study subject. Clinical data of the child were retrospectively collected. Peripheral blood samples were collected from the child and his parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing of the family members. Pathogenicity of the variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the effect of the NONO gene variant on messenger RNA (mRNA) expression level in the proband, and complementary DNA (cDNA) sequencing was performed to validate the splicing patterns of the NONO gene variant in the proband. Using the keywords "NONO gene" "MRXS34" "developmental delay" "intellectual disability" and "congenital heart disease", a literature search was conducted in databases including the China National Knowledge Infrastructure(CNKI), Wanfang Data and PubMed databases to identify studies on the clinical and genotypic characteristics of children with MRXS34 caused by NONO gene variants. The search period was set from the inception of the databases to April 2025, and a comprehensive analysis of the findings from the identified studies was performed. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: IRB-KYHZ-2019-006). RESULTS: The proband, a 3-year-old male, exhibited global developmental delay, intellectual disability, facial dysmorphism, macrocephaly, corpus callosum dysgenesis, cavum septum pellucidum, atrial septal defect, tricuspid valve insufficiency with regurgitation, cryptorchidism, inguinal hernia, and anal cutaneous fistula. The results of WES and Sanger sequencing validation showed that the proband carried a heterozygous variant of the NONO gene c.577_581del (p.Val193fs), while both parents were wild-type, indicating that this variant was a de novo variant. According to the ACMG guidelines, this variant was classified as pathogenic (PVS1+PS2_Moderate+PM2_Supporting). RT-qPCR results showed that the relative mRNA expression level of the NONO gene in the proband was significantly lower than that in the control group of normal children, and cDNA sequencing results verified that the frameshift variant due to base deletion led to nonsense-mediated mRNA decay (NMD), causing premature termination of transcription without exon skipping at the splice site. Using the literature search strategy established in this study, a total of 15 studies on the clinical and genotypic characteristics of children with MRXS34 caused by NONO gene variants were identified, involving a total of 32 patients. Together with the proband of this study, a total of 33 patients were included in the comprehensive analysis. The results revealed a total of 23 types of variants involving the NONO gene. The main clinical manifestations of MRXS34 included developmental delay/intellectual disability (23/24, 95.8%), cardiovascular abnormalities (23/30, 76.7%), craniofacial/somatic malformations (21/24, 87.5%), and corpus callosum dysgenesis (16/21, 76.2%). CONCLUSION: The NONO gene variant probably underlay the pathogenesis of MRXS34 in this proband. The findings of this study has expanded of the variant and clinical spectra associated with the NONO gene.

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