Clinician’s Guide to Congenital Heart Disease Genetics

Blue GM, Kirk EP, Giannoulatou E, et al.
Advances in the Genetics of Congenital Heart Disease: A Clinician’s Guide. J Am Coll Cardiol 2017;69:859-870.

The following are key points to remember from this review article on advances in the genetics of congenital heart disease (CHD):

  1. New genetic techniques have resulted in a rapidly expanding understanding of the genetics of congenital heart disease (CHD).
  2. While early studies focused on familial CHD, current efforts focus on an understanding of the genetics of sporadic disease.
  3. Genome-wide association studies (GWAS), which examine a genome-wide set of genetic variants in different individuals, led to the identification of associations between a number of genomic regions and CHD risk, including for atrial septal defect, tetralogy of Fallot, and left-sided CHD. However, GWAS have explained only a small population of the population-attributable risk for such lesions.
  4. With the technique of massively parallel sequencing (MPS), many sources of variation can be identified, including common and rare variants, insertions and deletions, and copy number variations.
  5. MPS studies have suggested that not all seemingly Mendelian forms of CHD are due to single gene mutations.
  6. Studies have shown the importance of de novo variants in sporadic CHD development, particularly in CHD cases associated with neurodevelopmental disabilities. This is important in light of clinical studies demonstrating the impact of pre-existing factors as opposed to clinical course in the determination of neurodevelopmental outcomes in patients with CHD.
  7. The ability of MPS to identify both rare and common variants is likely to discover additional associations between genotype and long-term outcomes. This will enable providers to individualize care and optimize treatment.
  8. In familial CHD, variants in known genes account for 31-46% of disease, while the cause remains unknown in 54-69%.
  9. In sporadic CHD, approximately 10% are thought to be de novo, 3-10% are related to copy number variation, and 80% are due to unknown cause.
  10. In CHD associated with extracardiac congenital anomalies, 25% are due to copy number variation, 26% due to single gene variations, and 49% are of unknown cause.
  11. At the current time, genetic testing for sporadic CHD is low-yield, although major advances are expected in upcoming years.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Congenital Heart Disease

Keywords: Genetic Testing, Genome, Genome-Wide Association Study, Genotype, Heart Defects, Congenital, Heart Septal Defects, Atrial, High-Throughput Nucleotide Sequencing, Mutation, Tetralogy of Fallot

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