A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient

Yuan, Zhongwei; Fan, Liang‐Liang; Jiang, Zichen; Yang, Yifeng; Tan, Zhiping

doi:10.3389/fcvm.2020.582350

Cited by 9 publications

(11 citation statements)

References 19 publications

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“…Dextrocardia is actually a failed developmental consequence of the left‐right asymmetry pattern, resulting in an alternative anatomy 20 . The common anatomy malformations include atrial septal defects, ventricular septal defects, valvular abnormalities, tetralogy of Fallot, and transposition of the great arteries, causing some electrophysiological changes 21–23 .…”

Section: Discussionmentioning

confidence: 99%

“…Dextrocardia is actually a failed developmental consequence of the left-right asymmetry pattern, resulting in an alternative anatomy. 20 The common anatomy malformations include atrial septal defects, ventricular septal defects, valvular abnormalities, tetralogy of Fallot, and transposition of the great arteries, causing some electrophysiological changes. [21][22][23] For instance, due to the discordance of the atrium and ventricle, some supraventricular tachycardia patients with dextrocardia and congenital corrected transposition of the great arteries had a secondary atrioventricular node, which precipitated two QRS morphologies, rending the junction of the pulmonary and mitral annulus as the catheter ablation target of the slow conduction pathway.…”

Section: Routine Visualization and Three-dimensional Reconstruction I...mentioning

confidence: 99%

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Result and technique consideration of radiofrequency catheter ablation of tachycardia in patients with dextrocardia

Zhang

Sun

Luo

et al. 2022

Pacing Clinical Electrophis

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Background: Patients with tachycardia, in the context of pre-existing dextrocardia, could benefit from catheter ablation. However, anatomical complexities hinder effective conduct of this procedure. We aimed to retrospectively summarize the clinical characteristics and the safety and efficiency, and recommended the technique considerations.Methods: Twenty-one cases from 19 patients with tachycardia and dextrocardia, who underwent catheter ablation between 2009 and 2021, were enrolled. All patients underwent echocardiography and computed tomography (CT) to confirm the anatomical malformations. Transseptal puncture was guided by fluoroscopy or intracardiac echocardiography when left atrial access was necessary and the ablation process was guided by three-dimensional (3D) mapping.Results: Six cases exhibited situs solitus while nine cases exhibited situs inversus. Fourteen cases had atrial fibrillation, seven had atrial flutter, and two had atrioventricular reentrant tachycardia (AVRT); two cases had combined atrial fibrillation and atrial flutter. Acute success was achieved in 18 cases (85.7%, 18/21). The 3D mapping system was not employed in the three cases which failed. During long-term follow-up (20.71 ± 21.86 months), eight cases (72.7%, 8/11) of atrial fibrillation with dextrocardia successfully attained sinus rhythm. None of AVRT cases had recurrence. Half of the atrial flutter cases with dextrocardia, especially those with a history of surgical correction for cardiac malformations, underwent recurrence. One case had cardiac tamponade. Conclusions:Catheter ablation for tachycardia patients with dextrocardia is safe, efficient, and feasible. It is imperative to integrate echocardiography, cardiac computer tomography, and 3D mapping, and apply 3D reconstruction to facilitate the success of catheter ablation.

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Section: Discussionmentioning

confidence: 99%

Section: Routine Visualization and Three-dimensional Reconstruction I...mentioning

confidence: 99%

Result and technique consideration of radiofrequency catheter ablation of tachycardia in patients with dextrocardia

Zhang

Sun

Luo

et al. 2022

Pacing Clinical Electrophis

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“…Mutations in genes encoding components of the BAF complex, such as ARID1B, ARID1A, ARID2, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, DPF2, and BICRA, cause a range of disorders, including syndromic intellectual disability, Coffin-Siris syndrome (CSS), and Nicolaides-Baraitser syndrome (NCBRS) (6,(12)(13)(14)(15)(16)(17)(18). Two terms, "SWI/SNF related intellectual disability disorders" (SSRIDDs) and "BAF-opathies, " have been proposed to represent the full range of these diseases (8,10).…”

Section: Discussionmentioning

confidence: 99%

“…Exomes were captured using Agilent SureSelect Human All Exon V6 kits and sequenced on an Illumina NovaSeq6000 (Illumina Inc., San Diego, USA). The WES data filtration strategy was based on previously published literature (10).…”

Section: Methodsmentioning

confidence: 99%

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome

Yuan

Xie

et al. 2021

Front. Cardiovasc. Med.

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Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort.Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions. The effects of the variant on ACTL6A RNA and protein were assessed using bioinformatics analysis.Results: At the start of the study, no mutations in known and candidate causative genes associated with CHD were identified. Seven years later, we noticed craniofacial deformities and identified a de novo heterozygous deletion variant in ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9). Intellectual disability and short stature were identified by a follow-up visit 10 years later. This variant leads to frameshift sequences and a premature termination codon and may affect the features of proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients.Conclusion: Our study reported the first ACTL6A variant in a Chinese individual, providing further evidence that ACTL6A is involved in heart and upper limb skeletal and intellectual development, thereby expanding the spectrum of ACTL6A variants. Thus, mutation analysis of the ACTL6A gene should be considered in patients with BAF-opathies or heart-hand syndromes due to potential misdiagnosis. Craniofacial dysmorphisms and intellectual disability are key to distinguishing these two diseases clinically, and attention to developmental delay/intellectual disability and craniofacial deformities will contribute to the diagnosis of BAF-opathies.

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“…Therefore, exome sequencing will be useful for screening novel pathogenetic candidates, expanding the mutational spectrum of patients with syndromic, non-syndromic, and sporadic HTX, ultimately providing a better understanding of the contribution of susceptible alleles to disease penetrance and pathogenesis. HTX-related pathogenic homozygous and compound heterozygous variants of MMP21 were detected in patients with HTX via exome sequencing [18,19,[29][30][31][32]; however, no studies reported whether simple heterozygous MMP21 variants can cause HTX. Thus, scanning the MMP21 variants in patients with HTX could help clarify the genotype-phenotype correlation and provide clues for genetic counseling.…”

Section: Introductionmentioning

confidence: 99%

De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children

Qin

Mengmeng

et al. 2022

Hum Genomics

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Background Heterotaxy syndrome (HTX) is caused by aberrant left–right patterning early in embryonic development, which results in abnormal positioning and morphology of the thoracic and abdominal organs. Currently, genetic testing discerns the underlying genetic cause in less than 20% of sporadic HTX cases, indicating that genetic pathogenesis remains poorly understood. In this study, we aim to garner a deeper understanding of the genetic factors of this disease by documenting the effect of different matrix metalloproteinase 21 (MMP21) variants on disease occurrence and pathogenesis. Methods Eighty-one HTX patients with complex congenital heart defects and 89 healthy children were enrolled, and we investigated the pathogenetic variants related to patients with HTX by exome sequencing. Zebrafish splice-blocking Morpholino oligo-mediated transient suppression assays were performed to confirm the potential pathogenicity of missense variants found in these patients with HTX. Results Three MMP21 heterozygous non-synonymous variants (c.731G > A (p.G244E), c.829C > T (p.L277F), and c.1459A > G (p.K487E)) were identified in three unrelated Chinese Han patients with HTX and complex congenital heart defects. Sanger sequencing confirmed that all variants were de novo. Cell transfection assay showed that none of the variants affect mRNA and protein expression levels of MMP21. Knockdown expression of mmp21 by splice-blocking Morpholino oligo in zebrafish embryos revealed a heart looping disorder, and mutant human MMP21 mRNA (c.731G > A, c.1459A > G, heterozygous mRNA (wild-type&c.731G > A), as well as heterozygous mRNA (wild-type& c.1459A > G) could not effectively rescue the heart looping defects. A patient with the MMP21 p.G244E variant was identified with other potential HTX-causing missense mutations, whereas the patient with the MMP21 p.K487E variant had no genetic mutations in other causative genes related to HTX. Conclusion Our study highlights the role of the disruptive heterozygous MMP21 variant (p.K487E) in the etiology of HTX with complex cardiac malformations and expands the current mutation spectrum of MMP21 in HTX.

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A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient

Cited by 9 publications

References 19 publications

Result and technique consideration of radiofrequency catheter ablation of tachycardia in patients with dextrocardia

Result and technique consideration of radiofrequency catheter ablation of tachycardia in patients with dextrocardia

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome

De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children

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