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Genetic and Epigenetic Mechanisms in the Development of Congenital Heart Diseases

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Genetic and Epigenetic Mechanisms in the Development of Congenital Heart Diseases Open access Review World Jnl Ped Surgery: first published as 10.1136/wjps-2020-000196 on 29 April 2021. Downloaded from Genetic and epigenetic mechanisms in the development of congenital heart diseases Yue Wu,1 Xiaosi Jin,2 Yuhao Zhang,3 Jing Zheng,1 Rulai Yang1 To cite: Wu Y, Jin X, Zhang Y, ABSTRACT surgical intervention techniques and peri- et al. Genetic and epigenetic Congenital heart disease (CHD) is the most common operative care has dramatically changed the mechanisms in the development of congenital cardiovascular malformations associated management of these populations with CHD. of congenital heart diseases. with birth defects, and it results in significant morbidity World Jnl Ped Surgery However, CHD is still a bothersome question and mortality worldwide. The classification of CHD is 2021;4:e000196. doi:10.1136/ owing to its undesirable outcomes and expen- still elusive owing to the complex pathogenesis of CHD. wjps-2020-000196 sive healthcare costs, which bring substantial Advances in molecular medicine have revealed the genetic physiological, emotional and socioeconomic ► Additional supplemental basis of some heart anomalies. Genes associated with material is published online only. CHD might be modulated by various epigenetic factors. challenges to patients, families and society. To view, please visit the journal Thus, the genetic and epigenetic factors are gradually According to the final anatomical and online (http:// dx. doi. org/ 10. 1136/ accepted as important triggers in the pathogenesis of pathophysiological complexities, CHD can wjps- 2020- 000196). CHD. However, few literatures have comprehensively be classified as mild, moderate or severe. 4 elaborated the genetic and epigenetic mechanisms of CHD. Detailed classification is shown in box 1. YW and XJ contributed equally. This review focuses on the etiology of CHD from genetics The prognosis, morbidity and mortality vary and epigenetics to discuss the role of these factors in the with the severity of the anomalies. Despite the Received 8 August 2020 development of CHD. The interactions between genetic and rapid advances in medical care and detection Revised 28 March 2021 epigenetic in the pathogenesis of CHD are also elaborated. technology, the etiology of most CHD remains Accepted 30 March 2021 Chromosome abnormalities and gene mutations in poorly understood. It is therefore imperative genetics, and DNA methylations, histone modifications and on-coding RNAs in epigenetics are summarized to improve our understanding of the disease in detail. We hope the summative knowledge of these mechanisms to reduce the frequent occur- etiologies may be useful for improved diagnosis and rence of CHD. During the past decades a further elucidation of CHD so that morbidity and mortality consensus has emerged that both genetic of children with CHD can be reduced in the near future. (eg, chromosomal abnormalities, smaller http://wjps.bmj.com/ © Author(s) (or their copy number variants and point mutations) employer(s)) 2021. Re- use and environmental (extrinsic factors, such as permitted under CC BY- NC. No commercial re- use. See rights INTRODUCTION teratogen exposure and nutrient deficiencies; and permissions. Published by Congenital heart disease (CHD) is a group of intrinsic factors, including maternal disease, 5 BMJ. disorders attributed by abnormalities in fetal illness and viral infection) factors are related 1 Department of Genetic and heart and large vessels that lead to actual or to the occurrence of CHD. Progress in molec- Metabolic Diseases, The potential impairment of cardiac function in ular genetic diagnosis has provided a valu- on September 28, 2021 by guest. Protected copyright. Children’s Hospital, Zhejiang University School of Medicine, infants. CHD is the most common type of able opportunity to investigate the genetic National Clinical Research congenital defect worldwide and is the most factors of CHD. Furthermore, a multitude Center for Child Health, common and the most life-threatening class of animal models (eg, mouse, zebrafish, frog Hangzhou, China and fruit fly) have witnessed the significant 2 of birth defects in infants, affecting approx- Department of Obstetrics, imately 1% live births annually worldwide.1 effects of genetic etiology of CHD. These in Hangzhou Women’s Hospital, Hangzhou First People’s Hospital Epidemiological investigations indicate that vivo studies on animal models, in turn, have Qianjiang New City Campus, the overall incidence of CHD varies across resulted in the identification of numerous Hangzhou, China countries and continents, and the preva- structural genes, transcriptional regulators 3 Cardiovascular Key Lab of lence of CHD in Asia is higher than that in and signaling molecules that are critical for Zhejiang Province, Department North America.2 Despite benefits from the normal cardiac morphogenesis.6 of Cardiology, The Second Affiliated Hospital, Zhejiang remarkable progress in therapeutic strategies To our knowledge, although numerous University School of Medicine, of surgery and catheter intervention, CHD literatures have discussed the genetic mech- Hangzhou, China is still the principal source of mortality in anisms of CHD, few have comprehensively infants. However, owing to medical, surgical elaborated the genetic and epigenetic mech- Correspondence to and technological evolutions during the past anisms of CHD. In this review, we focus on Dr Rulai Yang; chsczx@ zju. decades, more than 90% of CHD infants CHD origin from the etiology of genetics edu. cn now survive to adulthood.3 Improvement in and epigenetics. Chromosomal abnormalities Wu Y, et al. World Jnl Ped Surgery 2021;4:e000196. doi:10.1136/wjps-2020-000196 1 Open access World Jnl Ped Surgery: first published as 10.1136/wjps-2020-000196 on 29 April 2021. Downloaded from rapidly emerging data could provide a further under- Box 1 Classification of congenital heart disease the( standing of genetics and epigenetics in the development copyright can be viewed in the online supplemental file) of CHD and also a basis for further exploring the early Mild: diagnosis and individualized therapy of CHD. ► Isolated congenital aortic valve disease and bicuspid aortic disease. ► Isolated congenital mitral valve disease (except parachute valve and cleft leaflet). CHROMOSOME ABNORMALITIES UNDERLYING CHD ► Mild isolated PS (infundibular, valvular and supravalvular). Chromosome abnormalities refer to abnormal chro- ► Isolated small ASD, VSD or PDA. mosome numbers and structural aberrations including ► Repaired secundum ASD, sinus venosus defect, VSD or PDA without aneuploidies and copy number variations (CNVs), respec- residuae or sequellae, such as chamber enlargement, ventricular tively. Conventional chromosome anomalies associated dysfunction or elevated pulmonary artery pressure. with CHD were identified half a century ago. A study by Pierpont et al7 suggested that ~30% of children with Moderate (repaired or unrepaired where not specified; alphabetical order): a chromosomal abnormality would suffer from CHD. In ► Anomalous pulmonary venous connection (partial or total). the following section, we summarize the involvement of ► Anomalous coronary artery arising from the PA. chromosomal aneuploidies and CNVs in CHD in detail. ► Anomalous coronary artery arising from the opposite sinus. ► AS subvalvular or supravalvular. Aneuploidy in CHD ► AVSD, partial or complete, including primum ASD (excluding pulmo- Chromosomal aneuploidy is the earliest recognized nary vascular disease). genetic cause of CHD and accounts for a great propor- ► Coarctation of the aorta. tion of CHD (table 1). Approximately 50% of individ- Double- chambered right ventricle. ► uals born with trisomy 21 have the phenotypes of CHD, ► Ebstein anomaly. ranging from atrial septal defect (ASD)/ventricular ► Marfan syndrome and related HTAD and Turner syndrome. 1 2 ► PDA, moderate or large unrepaired (excluding pulmonary vascular septal defect (VSD) to atrioventricular canal lesions. disease). The prevalence of CHD in newborns with trisomy 13 and ► PPS. trisomy 18 increases to 80%, and the major phenotypes 8 9 ► PS (infundibular, valvular and supravalvular), moderate or severe. of CHD are heterotaxy, laterality and septal defects. ► Sinus of Valsalva aneurysm/fistula. CHD is observed in approximately 33% of females with ► Sinus venosus defect. Turner syndrome or monosomy X, and the cardiac ► TOF repaired. malformations are usually diagnosed as VSD, coarctation ► Transposition of the great arteries after arterial switch operation. of aorta (CoA), bicuspid aortic valve and hypoplastic left ► VSD with associated abnormalities (excluding pulmonary vascular heart.1 Although abnormal X chromosome numbers are disease) and/or moderate or greater shunt. rare, they also could result in CHD. For example, males with Klinefelter syndrome or 47, XXY have a 50% chance Severe (repaired or unrepaired where not specified; http://wjps.bmj.com/ alphabetical order): of CHD with the phenotypes of patent ductus arteriosus ► Any CHD (repaired or unrepaired) associated with pulmonary vas- (PDA) and ASD.7 Moreover, sporadic 49, XXXXX cases cular disease (including Eisenmenger syndrome). with the phenotypes of ASD and vascular malformations ► Any cyanotic CHD (unoperated or palliated). have also been reported.10 At present, chromosomal ► Double- outlet ventricle. G- banded karyotype analysis has been applied to detect Fontan circulation. ► the anomalies of chromosomes in spite of its limitation ► IAA. for the restrictive base resolution
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