Novel hemizygous loss‐of‐function variant in <scp><i>NONO</i></scp> identified in a South African boy

Coetzer, Kimberly Christine; Moosa, Shahida

doi:10.1002/ajmg.a.62509

Cited by 9 publications

(8 citation statements)

References 9 publications

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“…LVNC was the most common cardiac phenotype. We also found that LVNC is diagnosed early in almost all individuals (Table 1): six individuals who were pregnant, including the fetus we reported[6], four individuals who were in the neonatal period [3,5], and three individuals who were in infancy [2,4,9], indicating that LVNC is an early clue for diagnosing MRXS34 and emphasizing the importance of fetal echocardiography for identifying cardiac structural anomalies in NONO-related fetuses. impediment, which are characterized phenotypes of MRXS34 [1].…”

Section: Discussionmentioning

confidence: 54%

A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus

Huang,

Wu,

Ding

et al. 2024

Preprint

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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 loss-of-function variants in NONO reportedly cause X-linked syndromic intellectual developmental disorder-34 (MRXS34) in males. At present, there are few clinical reports related to MRXS34, and the mutation spectrum of NONO-related diseases has not been completely determined. Methods We report the case of a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly. Genotyping examination, including chromosome microarray analysis (CMA) and trio-medical exon sequencing, was performed. Results Medical exon sequencing revealed a de novo hemizygous nonsense mutation (c.214 C > T, p.Gln72Ter) in exon 4 of the NONO gene. A review of previous literature suggested that noncompaction cardiomyopathy, abnormalities of the corpus callosum, and macrocephaly are consistent phenotypes of MRXS34. Conclusion The mutation (c.214 C > T, p.Gln72Ter) in the NONO gene was present in a fetus with MRXS34. This study expands the mutation spectrum of NONO-related diseases and enlarges noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses.

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Section: Discussionmentioning

confidence: 54%

A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus

Huang,

Wu,

Ding

et al. 2024

Preprint

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“…With roles in almost every step of gene regulation 10 , Nono has diverse molecular functions, and it is gradually founded the clinically relevant in the contexts of cancer 25 , Innate immunity 26 , neurodevelopment 27 . Recently, it is reported worldwide that fifteen cases with cardiac phenotypes of LVNC and CHD have been found NONO loss-of-function variants 11 – 17 . To this date, there are no reports on the cardiac development of NONO .…”

Section: Discussionmentioning

confidence: 99%

“…As a multifunctional nuclear protein, NONO performs a variety of tasks involved in RNA synthesis, transcriptional activity, post-transcriptional regulation and DNA repair 10 . Emerging clinical evidences 11 – 17 showed that the loss-of-function variants of NONO could lead to left ventricular non-compaction (LVNC) and CHD, such as atrial septal defect (ASD), ventricular septal defect (VSD), Patent ductus arteriosus (PDA), pulmonary stenosis/pulmonary atresia (PS/PA), Ebstein's anomaly and Hypoplastic left heart syndrome in males. These suggested that NONO deficiency may influence cardiac development and lead to impaired cardiac structure and function.…”

Section: Introductionmentioning

confidence: 99%

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway

Lei

Wei

et al. 2023

Sci Rep

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Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. The non-POU domain containing, octamer-binding gene, NONO, performs a variety of roles involved in DNA repair, RNA synthesis, transcriptional and post-transcriptional regulation. Currently, hemizygous loss-of-function mutation of NONO have been described as the genetic origin of CHD. However, essential effects of NONO during cardiac development have not been fully elucidated. In this study, we aim to understand role of Nono in cardiomyocytes during development by utilizing the CRISPR/Cas9 gene editing system to deplete Nono in the rat cardiomyocytes H9c2. Functional comparison of H9c2 control and knockout cells showed that Nono deficiency suppressed cell proliferation and adhesion. Furthermore, Nono depletion significantly affected the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in H9c2 overall metabolic deficits. Mechanistically we demonstrated that the Nono knockout impeded the cardiomyocyte function by attenuating phosphatidyl inositol 3 kinase-serine/threonine kinase (Pi3k/Akt) signaling via the assay for transposase-accessible chromatin using sequencing in combination with RNA sequencing. From these results we propose a novel molecular mechanism of Nono to influence cardiomyocytes differentiation and proliferation during the development of embryonic heart. We conclude that NONO may represent an emerging possible biomarkers and targets for the diagnosis and treatment of human cardiac development defects.

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“…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%).…”

Section: Discussionmentioning

confidence: 99%

“…The authors suggested that LVNC may be part of this newly described syndrome [ 2 ]. 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 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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NONO (Non-Pou Domain-Containing Octamer-Binding Protein) gene maps on chromosome Xq13.1 and hemizygous loss-of-function nucleotide variants are associated with an emerging syndromic form of intellectual developmental disorder (MRXS34; MIM #300967), characterized by developmental delay, intellectual disability, poor language, dysmorphic facial features, and microcephaly. Structural brain malformation, such as corpus callosum and cerebellar abnormalities, and heart defects, in particular left ventricular non-compaction (LVNC), represent the most recurrent congenital malformations, recorded both in about 80% of patients, and can be considered the distinctive imaging findings of this disorder. We present on a further case of NONO-related disease; prenatally diagnosed in a fetus with complete corpus callosum agenesis; absence of septum pellucidum; pericallosal artery; LVNC and Ebstein’s anomaly. A high-resolution microarray analysis demonstrated the presence of a deletion affecting the NONO 3′UTR; leading to a marked hypoexpression of the gene and the complete absence of the protein in cultured amniocytes. This case expands the mutational spectrum of MRXS34, advises to evaluate NONO variants in pre- and postnatal diagnosis of subjects affected by LVNC and other heart defects, especially if associated with corpus callosum anomalies and confirm that CNVs (Copy Number Variants) represent a non-negligible cause of Mendelian disorders.

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Novel hemizygous loss‐of‐function variant in NONO identified in a South African boy

Cited by 9 publications

References 9 publications

A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus

A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway

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

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