Case Report: Characterization of a Novel NONO Intronic Mutation in a Fetus With X-Linked Syndromic Mental Retardation-34

Abstract

Background The NONO gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous variants in NONO have been reported to cause mental retardation, X-linked, syndromic 34 (MRXS34) in males. Due to the scarcity of clinical reports, the clinical characteristics and mutation spectrum of NONO-related disorder have not been entirely determined. Methods We reported a fetus with hypoplastic left heart syndrome, performed a comprehensive genotyping examination, including copy-number variation sequencing and whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted deleterious effects of an intronic variant of NONO. Results Exome sequencing identified a novel intronic variant (c.154 + 9A > G) in intron 4 of the NONO gene (NM_001145408.1). It was predicted to insert 4 bp of intron 4 into the mature mRNA. Minigene assay revealed that the c.154 + 9A > G variant caused the activation of the intronic cryptic splice site and 4 bp insertion (c.154_155ins GTGT) in mature mRNA. Literature review shows that cardiac phenotype, including left ventricular non-compaction cardiomyopathy and congenital heart disease, are consistent features of MRXS34. Conclusion This study enlarges the mutation spectrum of NONO, further expands hypoplastic left heart syndrome to the phenotype of MRXS34 and points out the importance of intronic sequence analysis and the need for integrative functional studies in the interpretation of sequence variants.

3′UTR Deletion of NONO Leads to Corpus Callosum Anomaly, Left Ventricular Non-Compaction and Ebstein’s Anomaly in a Male Fetus

“…Less clear is the involvement of NONO in heart defects that has been confirmed to be present in the most of NONO -patients. From the first description of a subjects with a pathogenic variant of NONO presenting with LVNC [ 2 ], this cardiac defect was reported in the other 12 male patients, making this clinical feature as a distinctive sign of this disorder [ 2 , 3 , 4 , 5 , 6 , 7 ]. Based on literature review, LVNC was isolated in two cases (2/13; 15%), whereas was reported in association with other structural heart defects in the others (11/13; 85%).…”

“…Effectively, since then, 73% of subjects affected by MRXS34 were reported showing cardiac anomalies, in particular LVNC, but also septal defects and right-sided lesions as Ebstein’s anomaly [ 3 , 4 , 5 , 6 ]. Heart defects were also disclosed as the peculiar clinical characteristic of a series of male fetuses with NONO variants detected by WES analysis [ 5 , 7 ]. Therefore, this characteristic associated with the neurodevelopmental phenotype could actually address the diagnosis of NONO -related disorder.…”

Case Report: A novel KNCH2 variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure

“…LQTS is a type of inherit cardiovascular disease that induces the prolonged duration of QT interval. Besides, some cases also demonstrated that LQTS presents as AVB (Aziz et al, 2010;Oka et al, 2010;Sun et al, 2022). It has been considered that AVB could be due to LQTS as a kind of pseudo AVB.…”

Genetic and phenotypic spectrum in the NONO‐associated syndromic disorder

“…To date, 10 live‐born and 7 prenatal cases with either maternally inherited or de novo null variants in NONO were reported in 14 families (Carlston et al, 2019; Mircsof et al, 2015; Reinstein et al, 2016; Scott et al, 2017; Sewani et al, 2020; Sun, Han, et al, 2020; Sun, Zhou, et al, 2020). Through international collaboration, we extended the published cohort by six live‐born males with NONO null variants, including the first in‐frame splice variant.…”