Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Xu, Jiahong; Gu, Jian-Yun; Guo, Yu-Han; Zhang, Hong; Qiu, Xing‐Biao; Li, Ruogu; Shi, Hongyu; Liu, Hua; Yang, Xiaoxiao; Xu, Ying‐Jia; Qu, Xinkai; Yang, Yi‐Qing

doi:10.1536/ihj.16-440

Cited by 19 publications

(7 citation statements)

References 52 publications

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“…In this regard, it is known that some patients have significant left ventricular hypoplasia in the absence of significant mitral or aortic stenosis. Consistent with this hypothesis, mutations in at least one gene, namely NKX2-5 , have been reported in association with both hypoplasia of the left heart and cardiomyopathy [11,12]. There are also reports of patients with the syndrome exhibiting so-called “non-compaction” of the right ventricle.…”

Section: Existing Concepts For Abnormal Morphogenesismentioning

confidence: 83%

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

Grossfeld

Nie

Lin

et al. 2019

JCDD

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Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. There is controversy surrounding the mechanisms underlying the syndrome, which is likely due, in part, to the phenotypic variability of the disease. The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. Research has also been hindered by what has been, up until now, a lack of genetically engineered animal models that faithfully reproduce the human disease. There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. In this review, we discuss the evidence demonstrating that, at least for a subset of cases, the chamber hypoplasia is the consequence of hyperplasia of the contained cardiomyocytes. In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome.

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Section: Existing Concepts For Abnormal Morphogenesismentioning

confidence: 83%

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

Grossfeld

Nie

Lin

et al. 2019

JCDD

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“…Several reports have described DCM onset occurring after the age of 40 years. 11,22,31,32) Therefore, long-term follow-up is needed to confirm whether there is a gender difference in this family. In addition, the influence of gender on the clinical severity of inherited cardiovascular disease caused by an autosomal monogenic mutation is still unclear and requires further investigation in a large cohort.…”

Section: Discussionmentioning

confidence: 99%

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

et al. 2018

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SummaryThe cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM. Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular diseaseassociated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.(Int Heart J 2018; 59: 531-541)

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“…Importantly, several of these factors contribute to multiple facets of cardiac development beyond just the early stages, such as for example chamber formation and valvulogenesis as reported for Nxk2.5 and Gata4 ( [11][12][13]), respectively. Furthermore, the functional roles of these early cardiogenic lineage transcription factors are also associated to adult cardiac structural pathologies, such as dilated cardiomyopathy [420][421][422][423][424][425][426] or bicuspid aortic valves [427,428] and electrophysiological pathologies such as atrial fibrillation [429][430][431][432]. Manipulation of these core transcription factors have provided new tools to convert differentiated cells such as fibroblasts into cardiomyocytes [91], opening new therapeutic opportunities to heal the damaged heart.…”

Section: Perspectivesmentioning

confidence: 99%

Cardiac Development: A Glimpse on Its Translational Contributions

Franco

García-Padilla

Domínguez

et al. 2021

Hearts

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Cardiac development is a complex developmental process that is initiated soon after gastrulation, as two sets of precardiac mesodermal precursors are symmetrically located and subsequently fused at the embryonic midline forming the cardiac straight tube. Thereafter, the cardiac straight tube invariably bends to the right, configuring the first sign of morphological left–right asymmetry and soon thereafter the atrial and ventricular chambers are formed, expanded and progressively septated. As a consequence of all these morphogenetic processes, the fetal heart acquired a four-chambered structure having distinct inlet and outlet connections and a specialized conduction system capable of directing the electrical impulse within the fully formed heart. Over the last decades, our understanding of the morphogenetic, cellular, and molecular pathways involved in cardiac development has exponentially grown. Multiples aspects of the initial discoveries during heart formation has served as guiding tools to understand the etiology of cardiac congenital anomalies and adult cardiac pathology, as well as to enlighten novels approaches to heal the damaged heart. In this review we provide an overview of the complex cellular and molecular pathways driving heart morphogenesis and how those discoveries have provided new roads into the genetic, clinical and therapeutic management of the diseased hearts.

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Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Cited by 19 publications

References 52 publications

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

Cardiac Development: A Glimpse on Its Translational Contributions

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