Genetics of Congenital Heart Disease

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Abstract

Congenital heart disease (CHD) is one of the most common birth defects. Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important for heart development. Recent studies have shown genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways play important roles in CHD pathogenesis. Elucidating the genetic etiology of CHD will help improve diagnosis and the development of new therapies to improve patient outcomes.

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Global birth prevalence of congenital heart defects 1970–2017: updated systematic review and meta-analysis of 260 studies

Yingjuan Liu, Sen Chen, Liesl Joanna Zuhlke … (2019)

Abstract Background Globally, access to healthcare and diagnostic technologies are known to substantially impact the reported birth prevalence of congenital heart disease (CHD). Previous studies have shown marked heterogeneity between different regions, with a suggestion that CHD prevalence is rising globally, but the degree to which this reflects differences due to environmental or genetic risk factors, as opposed to improved detection, is uncertain. We performed an updated systematic review to address these issues. Methods Studies reporting the birth prevalence of CHD between the years 1970–2017 were identified from searches of PubMed, EMBASE, Web of Science and Google Scholar. Data on the prevalence of total CHD and 27 anatomical subtypes of CHD were collected. Data were combined using random-effect models. Subgroup and meta-regression analyses were conducted, focused on geographical regions and levels of national income. Results Two hundred and sixty studies met the inclusion criteria, encompassing 130 758 851 live births. The birth prevalence of CHD from 1970–2017 progressively increased to a maximum in the period 2010–17 of 9.410/1000 [95% CI (confidence interval) 8.602–10.253]. This represented a significant increase over the fifteen prior years (P = 0.031). The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions. In contrast the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased from 0.689/1000 (95% CI 0.607–0.776) in 1995–99, to 0.475/1000 (95% CI 0.392–0.565; P = 0.004) in 2010–17, which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered. There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429–5.696)] and Asia the highest [9.342/1000 (95% CI 8.072–10.704)]. Conclusions The reported prevalence of CHD globally continues to increase, with evidence of severe unmet diagnostic need in Africa. The recent prevalence of CHD in Asia for the first time appears higher than in Europe and America, where disease ascertainment is likely to be near-complete, suggesting higher genetic or environmental susceptibility to CHD among Asian people.

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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Sheng Jin, Jason Homsy, Samir Zaidi … (2017)

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.

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Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility.

Rusty Montgomery, Christopher Davis, Matthew Potthoff … (2007)

Histone deacetylases (HDACs) tighten chromatin structure and repress gene expression through the removal of acetyl groups from histone tails. The class I HDACs, HDAC1 and HDAC2, are expressed ubiquitously, but their potential roles in tissue-specific gene expression and organogenesis have not been defined. To explore the functions of HDAC1 and HDAC2 in vivo, we generated mice with conditional null alleles of both genes. Whereas global deletion of HDAC1 results in death by embryonic day 9.5, mice lacking HDAC2 survive until the perinatal period, when they succumb to a spectrum of cardiac defects, including obliteration of the lumen of the right ventricle, excessive hyperplasia and apoptosis of cardiomyocytes, and bradycardia. Cardiac-specific deletion of either HDAC1 or HDAC2 does not evoke a phenotype, whereas cardiac-specific deletion of both genes results in neonatal lethality, accompanied by cardiac arrhythmias, dilated cardiomyopathy, and up-regulation of genes encoding skeletal muscle-specific contractile proteins and calcium channels. Our results reveal cell-autonomous and non-cell-autonomous functions for HDAC1 and HDAC2 in the control of myocardial growth, morphogenesis, and contractility, which reflect partially redundant roles of these enzymes in tissue-specific transcriptional repression.

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Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 16 December 2019

Publication date Collection: December 2019

Volume: 9

Issue: 12

Electronic Location Identifier: 879

Affiliations

Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA; kyw13@ 123456pitt.edu (K.W.); jcc141@ 123456pitt.edu (J.C.)

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[* ]Correspondence: cel36@ 123456pitt.edu

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Kylia Williams https://orcid.org/0000-0003-1163-4546

Jason Carson https://orcid.org/0000-0003-1724-0492

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Publisher ID: biomolecules-09-00879

DOI: 10.3390/biom9120879

PMC ID: 6995556

PubMed ID: 31888141

SO-VID: 8931bc10-61b2-462e-82c8-2fd048cb3d24

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 01 November 2019

Date accepted : 09 December 2019

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Genetics of Congenital Heart Disease

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Most cited references 140

Global birth prevalence of congenital heart defects 1970–2017: updated systematic review and meta-analysis of 260 studies

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility.

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