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  • Review Article
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Genomic frontiers in congenital heart disease

Nature Reviews Cardiology volume 19, pages 26–42 (2022)Cite this article

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Abstract

The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in the developing heart and depletion of damaging protein-coding variants in the general population. Gene classes fulfilling these criteria are enriched in patients with CHD and extracardiac abnormalities, evidencing shared pathways in organogenesis. Developmental single-cell transcriptomic data demonstrate the expression of CHD-associated genes in particular cell lineages, and emerging insights indicate that genetic variants perturb multicellular interactions that are crucial for cardiogenesis. Whole-genome sequencing analyses extend these observations, identifying non-coding variants that influence the expression of genes associated with CHD and contribute to the estimated ~55% of unexplained cases of CHD. These approaches combined with the assessment of common and mosaic genetic variants have provided a more complete knowledge of the causes and mechanisms of CHD. Such advances provide knowledge to inform the clinical care of patients with CHD or other birth defects and deepen our understanding of the complexity of human development. In this Review, we highlight known and candidate CHD-associated human genes and discuss how the integration of advances in developmental biology research can provide new insights into the genetic contributions to CHD.

Key points

  • A genetic risk contributes substantially to congenital heart disease (CHD), and variants in >400 genes are estimated to cause human CHD.

  • Analyses of large cohorts of patients with CHD have empowered the identification of novel genes associated with human CHD.

  • Non-coding variants contribute to CHD, in part by altering the activity of cardiac developmental enhancers.

  • Despite the genetic insights gained so far, a definitive cause is not identified in half of the cases of CHD.

  • Integration of genomic data with developmental biology promises to increase our understanding of the pathogenesis of CHD.

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Fig. 1: Common types of congenital heart disease.
Fig. 2: Human heart development.
Fig. 3: Definitive and candidate genes for congenital heart disease: genes with LOF variants.
Fig. 4: Definitive and candidate genes for congenital heart disease: genes with damaging missense variants.
Fig. 5: Relationship between extracardiac features, genotypes and functions of CHD-associated genes.
Fig. 6: Cardiac lineage-specific and temporal expression of definitive and candidate genes for CHD.

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Acknowledgements

The authors’ work is supported in part by grants from the Harvard Medical School Epigenetics & Gene Dynamics Award, AHA postdoctoral Fellowship, and Boston Children’s Hospital Office of Faculty Development Career Development Fellowship Award (S.U.M.), the John S. LaDue Memorial Fellowship at Harvard Medical School (D.Q.), National Institutes of Health (J.G.S.: UM1 HL098166, HL151257; C.E.S.: UM1 HL0981479, 3U01HL131003), and the Howard Hughes Medical Institute (C.E.S.).

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  1. These authors contributed equally: Sarah U. Morton, Daniel Quiat.

Authors and Affiliations

  1. Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Boston, MA, USA

    Sarah U. Morton

  2. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Sarah U. Morton & Daniel Quiat

  3. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Sarah U. Morton, Daniel Quiat, Jonathan G. Seidman & Christine E. Seidman

  4. Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA

    Daniel Quiat

  5. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Christine E. Seidman

  6. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA

    Christine E. Seidman

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Related links

American College of Medical Genetics and Genomics: https://www.acmg.net/

ClinGen: https://clinicalgenome.org

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Genome Aggregation Database: https://gnomad.broadinstitute.org/

Online Mendelian Inheritance in Man: https://www.omim.org/

Supplementary information

Glossary

Whole-exome sequencing

(WES). Targeted sequencing of protein-encoding regions, which comprise 1% of the genome. WES can be used to determine single-nucleotide variants, small insertions and deletions, and copy number variants, but is less sensitive than WGS for the detection of structural variants.

Whole-genome sequencing

(WGS). Sequencing of the entire genome (protein coding and non-coding regions) that can be used to determine single-nucleotide variants, small insertions and deletions, and structural variants.

Probability of LOF intolerance

(pLI). A measure of evolutionary constraint estimated by the ratio of observed LOF variant alleles in the gnomAD cohort compared with the expected number of LOF variants on the basis of mutation rate, cohort size and sequence context.

Genome-wide association studies

A statistical genetic analysis approach that associates common genetic variants, often with a minor allele frequency of ≥5%, with quantitative and qualitative traits. Given the number of genomic loci, a commonly accepted significance threshold of P < 5 × 10−8 is used regardless of how many loci are included in the analysis.

Alternative allele fraction

The proportion of total nucleotide reads at a particular genomic position that represent a non-reference allele. For example, in a sequencing library containing ten reads of the reference allele A and ten reads of the alternative allele T, the alternative allele fraction would be 0.5 (10/20).

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Morton, S.U., Quiat, D., Seidman, J.G. et al. Genomic frontiers in congenital heart disease. Nat Rev Cardiol 19, 26–42 (2022). https://doi.org/10.1038/s41569-021-00587-4

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