Genetics and Epigenetics of Human Congenital Heart Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 May 2021) | Viewed by 31018

Special Issue Editors


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Guest Editor
Department of Developmental Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
Interests: human congenital heart disease; genetics and epigenetics; left-right patterning in cardiovascular development; mouse forward genetic screens

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Guest Editor
Alnylam Pharmaceuticals, Cambridge, MA 02139, USA
Interests: congenital heart disease, genetics, cardiac amyloidosis, ATTR (transthyretin) amyloidosis, RNAi therapy

Special Issue Information

Congenital heart disease (CHD), a birth defect involving structural anomalies of the cardiovascular system, is one of the most common birth defects. Clinical studies and analysis of mouse models have shown a genetic etiology for CHD. The finding of incomplete penetrance and variable expressivity would suggest the involvement of complex genetics and with additional modifying effects from epigenetic mechanisms such as DNA methylation or chromatin modifications. While many genes have now been identified to contribute to CHD, the genetic architecture of CHD is still poorly understood. Moreover, gene-environment interactions are likely important contributing factors impacting the risk of having CHD, such as with chemical exposures, folate deficiencies, or diet. Furthermore, recent work suggests CHD penetrance can be modified by maternal exercise, suggesting as yet other unknown epigenetic mechanisms impacting CHD penetrance. With surgical advances now allowing more adults to survive with CHD there is also the realization that CHD patients surviving to adulthood often suffer neurocognitive impairment, neurobehavioral deficits, increased risk of Alzheimer’s disease, heart failure, renal dysfunction, and other defects.  Hence insights into the genetic and epigenetic mechanisms contributing to CHD is very much needed to help elucidate the molecular mechanism driving not only the cardiovascular defects, but also the clinical sequela associated with CHD. Only with mechanistic insights gained will it be possible to develop evidence-based therapies to prevent or improve the long term outcomes of CHD patients surviving their critical structural heart defects.

Prof. Dr. Cecilia Lo
Dr. Patrick Jay
Guest Editors

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Keywords

  • Genetics
  • Epigenetics
  • Congenital heart disease
  • DNA methylation
  • Chromatin
  • Penetrance
  • Expressivity
  • Exercise
  • Folate
  • Chemical exposure

Published Papers (9 papers)

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Research

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11 pages, 2138 KiB  
Article
Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta
by Wenjuan Zhu, Kylia Williams, Cullen Young, Jiaunn-Huey Lin, Polakit Teekakirikul and Cecilia W. Lo
Genes 2022, 13(4), 636; https://doi.org/10.3390/genes13040636 - 2 Apr 2022
Cited by 5 | Viewed by 2430
Abstract
Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the [...] Read more.
Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare MYH6 variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (PCDHA delCNVs) are significantly associated with CoA and BAV. Here, analysis of a non-Icelandic white CHD cohort (n = 166) recovered rare MYH6 variants in 10.9% of CoA and 32.7% of BAV/CoA patients, yielding odds ratios of 18.6 (p = 2.5 × 10−7) and 20.5 (p = 7.4 × 10−5) for the respective association of MYH6 variants with CoA and BAV/CoA. In combination with the PCHDA delCNVs, they accounted for a third of CoA cases. Gene expression datasets for the human and mouse embryonic heart showed that both genes are predominantly expressed in the atria, not the ventricle. Moreover, cis-eQTLs analysis showed the PCHDA delCNV is associated with reduced atrial expression of PCHDA10, a gene in the delCNV interval. Together, these findings showed that PCDHA/MYH6 variants account for a substantial fraction of CoA cases. An atrial rather than ventricular hemodynamic model for CoA is indicated, consistent with the known early atrial functional dominance of the human embryonic heart. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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20 pages, 3682 KiB  
Article
Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays
by Kalyani B. Karunakaran, George C. Gabriel, Narayanaswamy Balakrishnan, Cecilia W. Lo and Madhavi K. Ganapathiraju
Genes 2022, 13(4), 627; https://doi.org/10.3390/genes13040627 - 1 Apr 2022
Cited by 1 | Viewed by 2826
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein–protein interactions (PPIs) using our High-Precision [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein–protein interactions (PPIs) using our High-Precision Protein–Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities. A total of 364 genes including 73 novel interactors were differentially regulated in tissue/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. We found that 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer’s disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy- and microcephaly-associated genes, with the shared genes enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways, respectively. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly, respectively. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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14 pages, 2022 KiB  
Article
The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost
by Ehiole Akhirome, Suk D. Regmi, Rachel A. Magnan, Nelson Ugwu, Yidan Qin, Claire E. Schulkey, James M. Cheverud and Patrick Y. Jay
Genes 2021, 12(9), 1368; https://doi.org/10.3390/genes12091368 - 31 Aug 2021
Cited by 1 | Viewed by 2297
Abstract
In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/− mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes [...] Read more.
In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/− mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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20 pages, 420 KiB  
Article
Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature
by Benjamin M. Helm, Benjamin J. Landis and Stephanie M. Ware
Genes 2021, 12(8), 1244; https://doi.org/10.3390/genes12081244 - 14 Aug 2021
Cited by 11 | Viewed by 2571
Abstract
The use of clinical genetics evaluations and testing for infants with congenital heart defects (CHDs) is subject to practice variation. This single-institution cross-sectional study of all inpatient infants with severe CHDs evaluated 440 patients using a cardiovascular genetics service (2014–2019). In total, 376 [...] Read more.
The use of clinical genetics evaluations and testing for infants with congenital heart defects (CHDs) is subject to practice variation. This single-institution cross-sectional study of all inpatient infants with severe CHDs evaluated 440 patients using a cardiovascular genetics service (2014–2019). In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were diagnostic in syndromic (N = 35) or isolated (N = 20) presentations. Genetic diagnoses were made in all CHD classes. Diagnostic yield was higher in syndromic appearing infants, but geneticists’ dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had diagnostic CMA. Interestingly, diagnostic results (15.8%) in left ventricular outflow tract obstruction (LVOTO) defects occurred most often in patients with isolated CHD. Geneticists’ evaluations were particularly important for second-tier molecular testing (10.5% test-specific yield), bringing the overall genetic testing yield to 17%. We assess these results in the context of previous studies. Cumulative evidence provides a rationale for comprehensive, standardized genetic evaluation in infants with severe CHDs regardless of lesion or extracardiac anomalies because genetic diagnoses that impact care are easily missed. These findings support routine CMA testing in infants with severe CHDs and underscore the importance of copy-number analysis with newer testing strategies such as exome and genome sequencing. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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10 pages, 426 KiB  
Article
Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States
by Omobola O. Oluwafemi, Fadi I. Musfee, Laura E. Mitchell, Elizabeth Goldmuntz, Hongbo M. Xie, Hakon Hakonarson, Bernice E. Morrow, Tingwei Guo, Deanne M. Taylor, Donna M. McDonald-McGinn, Beverly S. Emanuel and A. J. Agopian
Genes 2021, 12(7), 1030; https://doi.org/10.3390/genes12071030 - 1 Jul 2021
Cited by 1 | Viewed by 2326
Abstract
Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation [...] Read more.
Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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12 pages, 262 KiB  
Article
Common Variation in Cytoskeletal Genes Is Associated with Conotruncal Heart Defects
by Fadi I. Musfee, A. J. Agopian, Elizabeth Goldmuntz, Hakon Hakonarson, Bernice E. Morrow, Deanne M. Taylor, Martin Tristani-Firouzi, W. Scott Watkins, Mark Yandell and Laura E. Mitchell
Genes 2021, 12(5), 655; https://doi.org/10.3390/genes12050655 - 27 Apr 2021
Cited by 2 | Viewed by 2168
Abstract
There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate [...] Read more.
There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate gene-set analyses of rare variants have provided insight into the genetics of CHDs. However, similar analyses have not been conducted using data on common genetic variants. Consequently, we conducted common variant analyses of 15 CHD candidate gene-sets, using data from two common types of CHDs: conotruncal heart defects (1431 cases) and left ventricular outflow tract defects (509 cases). After Bonferroni correction for evaluation of multiple gene-sets, the cytoskeletal gene-set was significantly associated with conotruncal heart defects (βS = 0.09; 95% confidence interval (CI) 0.03–0.15). This association was stronger when analyses were restricted to the sub-set of cytoskeletal genes that have been observed to harbor rare damaging genotypes in at least two CHD cases (βS = 0.32, 95% CI 0.08–0.56). These findings add to the evidence linking cytoskeletal genes to CHDs and suggest that, for cytoskeletal genes, common variation may contribute to the risk of CHDs. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)

Review

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12 pages, 1385 KiB  
Review
Molecular Genetics and Complex Inheritance of Congenital Heart Disease
by Nicholas S. Diab, Syndi Barish, Weilai Dong, Shujuan Zhao, Garrett Allington, Xiaobing Yu, Kristopher T. Kahle, Martina Brueckner and Sheng Chih Jin
Genes 2021, 12(7), 1020; https://doi.org/10.3390/genes12071020 - 30 Jun 2021
Cited by 49 | Viewed by 8508
Abstract
Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number [...] Read more.
Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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13 pages, 642 KiB  
Review
From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects
by Martin Broberg, Johanna Hästbacka and Emmi Helle
Genes 2021, 12(6), 921; https://doi.org/10.3390/genes12060921 - 16 Jun 2021
Cited by 6 | Viewed by 3358
Abstract
Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized [...] Read more.
Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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14 pages, 682 KiB  
Review
Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects
by Lisa J. Martin and D. Woodrow Benson
Genes 2021, 12(6), 827; https://doi.org/10.3390/genes12060827 - 28 May 2021
Cited by 10 | Viewed by 3221
Abstract
Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed [...] Read more.
Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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