THE ROLE OF GENETICS IN THE UNDERSTANDING OF COMPLEX CONGENITAL HEART DISEASES

One of the most dynamic organs in the human body is the heart. Cardiac development is regulated by two key factors including signaling and transcriptional pathways. Thus, during the development of the fetus, any factor that disrupts the normal functioning of these factors may lead toward congenital heart defects (CHDs). Congenital heart disease is a complex multifactorial disease that involves both environmental and genetic factors.1,2 It is defined as any defect that occurs during heart development either in the cardiac structure or its associated vessels.3 Globally, it is one of the most common reasons for infant mortality and one of the most common birth defects in paediatric patients. As a rough estimate, 8 infants in every thousand live births are born with this fatal disease.4 Every year, in Pakistan approximately 40,000 children suffered from CHDs.5 Clinically depending upon the disease severity congenital heart diseases can be divided into two major subgroups one is non-syndromic and the other is syndromic. And among all these defects cardiac septation defects are the most common accounting for approximately 50% of the cases.6 It can be further sub-grouped as isolated lesions or complex diseases in combination with other heart defects.3 The exact mechanism involved in the pathogenesis of the congenital heart remains poorly understood but the most probable mechanism is multifactorial. Recent investigations suggest the role of epigenetic factors, micro RNA and small non-coding RNAs in the development of congenital heart defects. Moreover, advancements in molecular techniques including next-generation sequencing (NGS) helps in further detecting the genetic causes of CHDs such as the novel single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).7 The current approaches used for genetic diagnosis of paediatric patients suffering from CHDs include karyotype analysis, copy number variation analysis, next-generation sequencing, and whole-genome or whole-exome sequencing. The targeted NGS relies on the selected region of know gene of interest and compared to whole genome or exome sequencing it provides us deeper gene coverage with easy variant detection at a lower cost. It provides robust detection of deletions, insertion and single nucleotide polymorphisms which chromosomal microarray analysis (CMA) and karyotyping cannot detect. To date, many pathogenic variants in different genes such as CITED2, CHD7, ZFPM2, MYH6 and KMT2D have been investigated by using targeted NGS. While whole-exome or genome sequencing help in the discovery of genes involves in the pathogenesis of congenital heart defects as it gives us more resolution at a single base-pair level. Thus accurate genetic diagnosis can be done by using the appropriate diagnostic techniques that can ultimately help in better patient counseling and clinical outcome.8 Furthermore, personalized medicines or finding mutations responsible for individual congenital heart disease patients can direct to better outcomes and approaches for each cardiac malformation phenotype. Thus, ultimately combined data of patients genotypic and phenotypic following well-designed guidelines will accelerate the translation of each SNP information into better treatment and clinical insights.9 Keywords: NGS, Single nucleotide polymorphisms, CHDs. References Ashiq S, Ashiq K. Genetic perspective of the congenital heart disease. Pak Heart J. 2020;53(3):1-3. Wang H, Liu Y, Li Y, Wang W, Li L, Meng M, et al. Analysis of NKX2-5 in 439 Chinese patients with sporadic atrial septal defect. Medical Sci Monit. 2019;25:2756. Ashiq S, Ashiq K, Sabar MF. The role of NKX2-5 gene polymorphisms in congenital heart disease (CHD): a systematic review and meta-analysis. Egypt Heart J. 2021;73(1):1-9. Zhao M, Diao J, Huang P, Li J, Li Y, Yang Y, et al. Association of maternal diabetes mellitus and polymorphisms of the NKX2. 5 gene in children with congenital heart disease: a single centre-based case-control study. J Diabetes Res. 2020;2020:3854630. Hussain S, Sabir MU, Afzal M, Asghar I. Incidence of congenital heart disease among neonates in a neonatal unit of a tertiary care hospital. J Pak Med Assoc. 2014;64(2):175-8. Wolf M, Basson CT. The molecular genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol. 2010;25(3):192. Muntean I, Togănel R, Benedek T. Genetics of congenital heart disease: past and present. Biochem Genet. 2017;55(2):105-23. Qiao F, Hu P, Xu Z. Application of next-generation sequencing for the diagnosis of fetuses with congenital heart defects. Curr Opin Obstet Gynecol. 2019;31(2):132-8. Pasipoularides A. The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants. J Thorac Dis. 2018;10(Suppl 17):S1923-29.

Peer Support Experienced by Mothers of Children With Congenital Heart Defects in Sweden

The aim of this study was to describe experiences of peer support among mothers of children with congenital heart defects. Ten mothers were interviewed through a semi-structured approach and interviews were analyzed with systematic text condensation. The respondents established various channels used for peer support and navigated between the channels depending on what type of information or support they needed. Through the channels, they found peers they developed strong friendships with and who they relied on for emotional support. Communicating with peers involved the reciprocal exchange of unique emotional support between peers who understand each other as well as the exchange of information derived from their collective knowledge, and thus, difficult to find without the help of peers. The findings illustrate the potential strengths of establishing reliable collaboration and liaisons between clinical units and peer support networks.

Tips and Tricks in Cardiac Surgical Anesthesia

For operations including coronary artery by-pass grafting (CABG), heart valve repair or replacement, ascending aorta surgeries, heart transplantation, and surgical correction of congenital heart defects, anesthesia management shares many similar concepts

Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study

Background The belief that genetics plays a major role in the pathogenesis of congenital heart defects (CHD) has grown popular among clinicians. Although some studies have focused on the genetic testing of foetuses with CHD in China, the genotype–phenotype relationship has not yet been fully established, and hotspot copy number variations (CNVs) related to CHD in the Chinese population are still unclear. This cohort study aimed to assess the prevalence of chromosomal abnormalities in Chinese foetuses with different types of CHD. Results In a cohort of 200 foetuses, chromosomal abnormalities were detected in 49 (24.5%) after a prenatal chromosome microarray analysis (CMA), including 23 foetuses (11.5%) with aneuploidies and 26 (13.0%) with clinically significant CNVs. The additional diagnostic yield following whole exome sequencing (WES) was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers. The chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group; however, the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNV detected in CHD foetuses was the 22q11.2 deletion, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, and duplications of 17q12. Conclusions CMA is the recommended initial examination for cases of CHD in prenatal settings, for both simple heart defects and isolated heart defects. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.