Characteristics of Cardiac Phenotype in Prenatal Familial Cases With
            <i>NONO</i>
            Mutations

Sun, Hairui; Zhou, Xiaoxue; Hao, Xiaoyan; Zhang, Ye; Zhang, Hongjia; He, Yihua

doi:10.1161/circgen.119.002847

Cited by 11 publications

(15 citation statements)

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“…Interestingly, while structural cardiac defects and LVNC have been reported in MRXS34 (Reinstein et al, 2016;Scott et al, 2016;Carlston et al, 2019;Sewani et al, 2019;Sun et al, 2020b), HLHS has not been previously associated with NONO-related disorders. Although this cardiac abnormality might be coincidentally present in the fetus herein described, previous frequent reports of other structural cardiac abnormalities suggest a possible involvement of the NONO defect.…”

Section: Discussionmentioning

confidence: 94%

“…It is expected to result in either an abnormal truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. In addition, the majority of reported patients with NONO mutations presented with CHD ( Mircsof et al, 2015 ; Reinstein et al, 2016 ; Scott et al, 2016 ; Carlston et al, 2019 ; Sewani et al, 2019 ; Sun et al, 2020b ) suggesting the association between NONO deficiency and CHD. In conclusion, we classified this NONO mutation as pathogenic according to the American College of Medical Genetics and Genomics guidelines ( Richards et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is a highly conserved member of the Drosophila behavior/human splicing protein family thought to be involved in RNA synthesis, transcriptional regulation, and DNA repair ( Shav-Tal and Zipori, 2002 ). Hemizygous mutations in NONO have recently been reported to cause mental retardation, X-linked, syndromic 34 (MRXS34; OMIM: 300967) in several male patients ( Mircsof et al, 2015 ; Reinstein et al, 2016 ; Scott et al, 2016 ; Carlston et al, 2019 ; Sewani et al, 2019 ; Sun et al, 2020b ). The predominant presentation for these patients described so far is that of an X-linked recessive disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 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.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…From October 2010 to December 2019, 40 patients with a diagnosis of NCCM in the report were reviewed, and 37 patients fit our inclusion criteria, including five previously published patients with NONO mutations (20). Three cases were excluded for incomplete imaging or lack of evidence for NCCM.…”

Section: Resultsmentioning

confidence: 99%

“…This sequencing strategy led to a sweeping landscape of genetic variation of NCCM because of the ability to assess chromosomal abnormalities and identify novel candidate genes, rather than just sequencing the known NCCM genes. This advantage is well illustrated in cases with LoF variants in the NONO gene ( Table 2) (20). At the time of initial analysis, NONO was not considered as a cardiomyopathy related gene in any published literature.…”

Section: Discussionmentioning

confidence: 99%

Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population

Sun

Hao

Wang

et al. 2021

Front. Cardiovasc. Med.

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Objectives: Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM.Methods: We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigated for gestational age at diagnosis, gender, left or biventricular involvement, associated cardiac phenotypes, outcomes, and genetic testing data.Results: We identified 37 fetuses with NCCM out of 49,898 fetuses, indicating that the incidence of NCCM in the fetal population was 0.07%. Of the 37 fetuses, 26 were male, ten were female and one was of unknown gender. NCCM involvement biventricle is the most common (n = 16, 43%), followed by confined to the left ventricle (n = 14, 38%). Nineteen (51%) had additional congenital heart defects, with right-sided lesions being the most common (n = 14, 74%), followed by ventricular septal defects (n = 10, 53%). Hydrops fetalis was present in 12 cases (32%), of which four were atypical (pericardial effusion only). Sequencing analysis was performed at autopsy (n = 19) or postnatally (n = 1) on 20 fetuses. Of the 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, nine (47%) had positive genetic results, including one with a pathogenic copy number variant and eight with pathogenic/likely pathogenic variants. Non-sarcomere gene mutations accounted for the vast majority (n = 7). In contrast, sarcomere gene mutations occurred in only one case (TPM1), and no mutations were identified in the three most common sarcomere genes (MYH7, TTN, and MYBPC3) of pediatric and adult patients. Pathogenic/likely pathogenic variants were significantly more frequent in fetuses with congenital heart defects than those without congenital heart defects.Conclusions: Our data demonstrate that fetal NCCM is a unique entity. Compared with pediatric and adult NCCM, fetal NCCM is more prone to biventricle involvement, more likely to be complicated with congenital heart defects, and has a distinct genetic spectrum.

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

Coetzer

Moosa

2021

American J of Med Genetics Pt A

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Hemizygous loss-of-function variants in the non-POU domain-containing, octamerbinding gene, NONO, cause X-linked mental retardation syndrome 34 (MRXS34).Here, we describe the 12th patient in the literature with this rare syndrome, the first affected male from sub-Saharan Africa. This South African patient presented with dysmorphic features, congenital cardiac abnormalities (Ebstein's anomaly, left ventricular non-compaction, and a VSD), and developmental delay. He was enrolled in our "Undiagnosed Disease Programme." Exome sequencing identified a novel hemizygous 14bp deletion in NONO, which he inherited from his unaffected, healthy mother. His features overlap with the previous patients described, lending more support to the assertion that MRXS34 is a recognizable, albeit rare, syndrome. The cardiac anomalies are particularly distinctive, which combined with a variety of other associated features, should prompt the inclusion of NONO-associated MRXS34 in the differential diagnosis.

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Characteristics of Cardiac Phenotype in Prenatal Familial Cases With NONO Mutations

Cited by 11 publications

References 5 publications

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

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

Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population

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

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