The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza; Yang, Runqiang; Risgaard, Bjarke; Køber, Lars; Haunsø, Stig; Tfelt-Hansen, Jacob

doi:10.1002/mgg3.182

Cited by 6 publications

(7 citation statements)

References 41 publications

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“…As these previously mentioned NUP155 missense mutations as well as dysregulated expression of other discrete nups have been associated with a variety of clinical cardiopathologies (5,10,14), this study was carried out to investigate the prevalence of reported NUP155 variants with potential cardiopathogenicity. To this end, we canvassed variants within the NHLBI Exome Sequencing Project along with data from gnomAD and dbNSFP databases to enhance prioritization of variants potentially implicated in cardiovascular disorders (15,16).…”

Section: Introductionmentioning

confidence: 99%

Protein Subdomain Enrichment of NUP155 Variants Identify a Novel Predicted Pathogenic Hotspot

Leonard

Preston

Gucwa

et al. 2020

Front. Cardiovasc. Med.

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Functional variants in nuclear envelope genes are implicated as underlying causes of cardiopathology. To examine the potential association of single nucleotide variants of nucleoporin genes with cardiac disease, we employed a prognostic scoring approach to investigate variants of NUP155, a nucleoporin gene clinically linked with atrial fibrillation. Here we implemented bioinformatic profiling and predictive scoring, based on the gnomAD, National Heart Lung and Blood Institute-Exome Sequencing Project (NHLBI-ESP) Exome Variant Server, and dbNSFP databases to identify rare single nucleotide variants (SNVs) of NUP155 potentially associated with cardiopathology. This predictive scoring revealed 24 SNVs of NUP155 as potentially cardiopathogenic variants located primarily in the N-terminal crescent-shaped domain of NUP155. In addition, a predicted NUP155 R672G variant prioritized in our study was mapped to a region within the alpha helical stack of the crescent domain of NUP155. Bioinformatic analysis of inferred protein-protein interactions of NUP155 revealed over representation of top functions related to molecular transport, RNA trafficking, and RNA post-transcriptional modification. Topology analysis revealed prioritized hubs critical for maintaining network integrity and informational flow that included FN1, SIRT7, and CUL7 with nodal enrichment of RNA helicases in the topmost enriched subnetwork. Furthermore, integration of the top 5 subnetworks to capture network topology of an expanded framework revealed that FN1 maintained its hub status, with elevation of EED, CUL3, and EFTUD2. This is the first study to report novel discovery of a NUP155 subdomain hotspot that enriches for allelic variants of NUP155 predicted to be clinically damaging, and supports a role for RNA metabolism in cardiac disease and development.

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Section: Introductionmentioning

confidence: 99%

Protein Subdomain Enrichment of NUP155 Variants Identify a Novel Predicted Pathogenic Hotspot

Leonard

Preston

Gucwa

et al. 2020

Front. Cardiovasc. Med.

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“…The gene encodes beta‐myosin heavy chain which plays a role in sarcomere formation and cardiac muscle function. Variants in MYH7 have been previously reported in association with a variety of cardiac anomalies including hypertrophic, dilated and restrictive cardiomyopathies, Ebstein anomaly, and left ventricular noncompaction (Abbasi et al., ). The patient was diagnosed with Ebstein anomaly; her father, who has mild Ebstein anomaly, was found to carry the variant as well.…”

Section: Resultsmentioning

confidence: 99%

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

Hauser

Solomon²,

Vilboux³

et al. 2018

Molec Gen & Gen Med

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BackgroundCongenital cardiac defects, whether isolated or as part of a larger syndrome, are the most common type of human birth defect occurring on average in about 1% of live births depending on the malformation. As there is an expanding understanding of the underlying molecular mechanisms by which a cardiac defect may occur, there is a need to assess the current rates of diagnosis of cardiac defects by molecular sequencing in a clinical setting.Methods and ResultsIn this report, we evaluated 34 neonatal and pediatric patients born with a cardiac defect and their parents using exomized preexisting whole genome sequencing (WGS) data to model clinically available exon‐based tests. Overall, we identified candidate variants in previously reported cardiac‐related genes in 35% (12/34) of the probands. These include clearly pathogenic variants in two of 34 patients (6%) and variants of uncertain significance in relevant genes in 10 patients (26%), of these latter 10, 2 segregated with clinically apparent findings in the family trios.ConclusionsThese findings suggest that with current knowledge of the proteins underlying CHD, genomic sequencing can identify the underlying genetic etiology in certain patients; however, this technology currently does not have a high enough yield to be of routine clinical use in the screening of pediatric congenital cardiac defects.

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“…In this novel study, we provide the clinicians the first comprehensive evaluation tool for genetic diagnostic of PAH, by evaluating the allele frequency of previously reported PAH‐associated variants in the two large background population databases (ESP and ExAC), and also by adding in silico prediction analysis using an established conservative method (Abbasi et al., ; Jabbari et al., ; Risgaard et al., ). Surprisingly, in the literature we identified very limited data on familial cosegregation, thus, unfortunately, the familial cosegregation in our evaluation was very limited.…”

Section: Discussionmentioning

confidence: 99%

“…Missense variants Nonsense variants BMPR2 86 49 population databases (ESP and ExAC), and also by adding in silico prediction analysis using an established conservative method (Abbasi et al, 2016;Jabbari et al, 2013;Risgaard et al, 2013). Surprisingly, in the literature we identified very limited data on familial cosegregation, thus, unfortunately, the familial cosegregation in our evaluation was very limited.…”

Section: Genementioning

confidence: 99%

Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension

Abbasi

Jabbari

et al. 2018

Molec Gen & Gen Med

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BackgroundWe aimed to provide a set of previously reported PAH‐associated missense and nonsense variants, and evaluate the pathogenicity of those variants.MethodsThe Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH‐associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH‐associated missense and nonsense variants. The pathogenicity of previously reported PAH‐associated missense variants evaluated by using four in silico prediction tools.ResultsIn total, 14 PAH‐associated genes and 180 missense and nonsense variants were gathered. The BMPR2, the most frequent reported gene, encompasses 135 of 180 missense and nonsense variants. The exome sequencing project comprised 9, and the exome aggregation consortium counted 25 of 180 PAH‐associated missense and nonsense variants. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis.ConclusionThis is the first evaluation of previously reported PAH‐associated missense and nonsense variants. The BMPR2 identified as the major gene out of 14 PAH‐associated genes. Based on findings, the ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH.

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The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Cited by 6 publications

References 41 publications

Protein Subdomain Enrichment of NUP155 Variants Identify a Novel Predicted Pathogenic Hotspot

Protein Subdomain Enrichment of NUP155 Variants Identify a Novel Predicted Pathogenic Hotspot

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension

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