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Human genetics of Congenital Heart Disease

Congenital heart disease (CHD) affects just under 1% of liveborn babies. Though the prognosis for patients born with CHD is now in general very good, there remains a need for multiple operations in some patients, and there is an increasingly recognised, but little understood, susceptibility to other health conditions in later life. Studies of CHD recurrence in families has shown a significant component of causation is due to genetic factors. These are still very substantially unknown, and in most cases families cannot be offered genetic tests that might tell them why the condition has occurred in their family. 

We have collected thousands of samples from patients with CHD and their families, and are using advanced genetic techniques including whole-exome and whole-genome sequencing to investigate the role of common and rare single nucleotide variants, and copy number variants, in CHD.  We collaborate with colleagues at the University of Cape Town, South Africa, to extend our studies to genetically diverse populations suffering CHD. We are also studying largescale population databases containing genetically characterised patients with CHD, for example the UK 100,000 Genomes Project, and the UK Biobank Study. In parallel we study global trends in the epidemiology of CHD. 
Among our contributions in this area are:

Williams SG, Byrne DJF, Keavney BD. Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes. J Hum Genet. 2022 Feb;67(2):123-125. doi: 10.1038/s10038-021-00976-0. Epub 2021 Sep 7. PMID: 34493817; PMCID: PMC8786659.

Liu Y, Chen S, Zühlke L, Black GC, Choy MK, Li N, Keavney BD. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019 Apr 1;48(2):455-463. doi: 10.1093/ije/dyz009. PMID: 30783674; PMCID: PMC6469300.

Sifrim A, Hitz MP, Wilsdon A, Breckpot J … Keavney B … Deciphering Developmental Disorders Study, Hurles ME. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016 Sep;48(9):1060-5. doi: 10.1038/ng.3627. Epub 2016 Aug 1. PMID: 27479907; PMCID: PMC5988037.

Cordell HJ, Bentham J, Topf A, Zelenika D … Farrall M, Goodship JA, Keavney BD. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. Nat Genet. 2013 Jul;45(7):822-4. doi: 10.1038/ng.2637. Epub 2013 May 26. PMID: 23708191; PMCID: PMC3793630.

Soemedi R, Wilson IJ, Bentham J, Darlay R … Cordell HJ, Goodship JA, Keavney BD. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet. 2012 Sep 7;91(3):489-501. doi: 10.1016/j.ajhg.2012.08.003. Epub 2012 Aug 30. PMID: 22939634; PMCID: PMC3511986.

Functional investigation of genes predisposing to CHD

Genome-wide association studies (GWAS) typically identify regions of the genome that are associated with disease, but do not pinpoint specific genes. We are working on the identification and characterisation of genes we identified in our GWAS studies, on chromosomes 4 and 13. Identification of new genetic influences on heart development is improving our understanding of the molecular circuitry that is involved in building a heart, and the reasons it can go wrong . 
Whole exome and whole-genome sequencing studies more directly implicate genes involved in CHD. We have discovered many of these genes, including recently determining the two most important in the causation of the cardiac outflow tract malformation Tetralogy of Fallot. We are investigating the signalling pathways implicated by these genes (NOTCH1 and FLT4)
We combine in vivo modelling in mice, with cellular and molecular biology, to investigate these genes. We prominently use human stem cells differentiated to the cell types prominently involved in constituting the embryonic heart (cardiomyocytes, neural crest cells, endothelial cells), and use CRISPR gene-editing to model “disease in a dish”. We are extending these experiments to organoid models constituted through co-culture of these cell types. 
We are interested in the role of long-range chromatin interaction in governing the expression of genes during heart development. Short non-coding DNA segments known as enhancers can interact with gene promoters over very large genomic distances; enhancers active in developmental stages may be involved in the mechanisms leading to CHD. We have shown that sites involved in long-range chromatin interaction map preferentially to regions associated with cognate cellular phenotypes in hESC-derived cardiomyocytes, and are exploring the capacity of these interactions to identify the regional gene responsible for a significant GWAS signal.

Among our contributions in this area are:

Fotiou E, Williams S, Martin-Geary A, Robertson DL, Tenin G, Hentges KE, Keavney B. Integration of Large-Scale Genomic Data Sources With Evolutionary History Reveals Novel Genetic Loci for Congenital Heart Disease. Circ Genom Precis Med. 2019 Oct;12(10):442-451. doi: 10.1161/CIRCGEN.119.002694. Epub 2019 Oct 15. PMID: 31613678; PMCID: PMC6798745.

Page DJ, Miossec MJ, Williams SG, Monaghan RM … Lathrop GM, Santibanez-Koref M, Keavney BD. Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. Circ Res. 2019 Feb 15;124(4):553-563. doi: 10.1161/CIRCRESAHA.118.313250. PMID: 30582441; PMCID: PMC6377791.

Choy MK, Javierre BM, Williams SG, Baross SL … Spivakov M, Fraser P, Keavney BD. Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks. Nat Commun. 2018 Jun 28;9(1):2526. doi: 10.1038/s41467-018-04931-0. Erratum in: Nat Commun. 2018 Nov 12;9(1):4792. PMID: 29955040; PMCID: PMC6023870.

Töpf A, Griffin HR, Glen E, Soemedi R … O'Sullivan J, Keavney BD, Goodship JA. Functionally significant, rare transcription factor variants in tetralogy of Fallot. PLoS One. 2014 Aug 5;9(8):e95453. doi: 10.1371/journal.pone.0095453. PMID: 25093829; PMCID: PMC4122343.

Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B. Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression. PLoS Genet. 2010 Apr 8;6(4):e1000899. doi: 10.1371/journal.pgen.1000899. PMID: 20386740; PMCID: PMC2851566.

Comorbidities in CHD

The fact that so many more people with CHD who would in the pre-surgical era have died in childhood, are now living a full lifespan, is a major medical achievement. But, recent evidence suggests that important comorbidities (co-existing medical conditions) may be more common in patients with CHD, even mild forms of CHD. The extent of this predisposition, and the reasons for it, remain very unclear at present. We are working in large population databases, for example the UK Clinical Practice Research Datalink (CPRD) to further explore these associations. In populations with genotypes available, from our own patient collections and the UK Biobank study, we are examining whether genetic factors could predispose both to CHD and other cardio-pulmonary comorbidity.

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