Genetic Architecture of Congenital Heart Disease: An Update and Future Challenges

Congenital heart disease (CHD), with an estimated incidence of 2-3% when bicuspid aortic valve is included, is widely believed to have strong genetic basis.¹

Nowadays, with advances in percutaneous and surgical interventions, approximately 90 % of infants born with CHD survive into adulthood. With increased life expectancy, it is fundamental to understand the genetic causes in order to prevent and guide management in the long-term as well as to provide family genetic counseling regarding on the recurrence risk.

However, CHD gene identification still represents a major challenge, because CHD etiology is complicated by the complex regulatory circuits of cardiogenesis as well as by phenotypic heterogeneity.

The American Heart Association Scientific Statement entitled “Genetic Basis for Congenital Heart Disease: Revisited” is an update of a previous document1 and a comprehensive contribution on this topic.²

The Writing Committee exhaustively reviews the most recent advancement in the field to update the previous statement.1 Wide information is given on the current genomic technologies including classical karyotyping analysis, fluorescent in situ hybridization analysis (FISH), array comparative genomic hybridization (array CGH) or single nucleotide polymorphism array (SNP array), copy-number variant (CNV) platforms and next-generation platforms.

The authors address, in depth, the genetic syndromes showing extracardiac additional malformations and various types of CHD due to classic chromosome number anomalies (e.g., Down syndrome, Turner syndrome), subchromosomal deletions and duplications or CNV (e.g., 22q11.2deletion; 1q21.1 duplication) and rare monogenic pathogenic mutations (e.g. Alagille, Holt-Oram,).

Moreover, the statement highlights recent discoveries and clinical features of other rare monogenic syndromic disorders, known as RASopathies (e.g. Noonan, Cardio-Facio-Cutaneous, Costello and Noonan with Multiple Lentigines syndromes) and heterotaxy/ciliopathies (syndromic ciliopathies, heterotaxy syndrome and primary ciliary dyskinesia), providing information on the known causative genes and their consequent heart involvement.

Moving forward, the statement discusses some recent insights into the complex genetic architecture of non-syndromic CHD. Indeed, most cases of CHD occurs sporadically in non-syndromic patients, and their genetic defect remain often unestablished.

Mendelian monogenic inheritance has been demonstrated in some sporadic types of CHDs, particularly in pedigrees with a clear familial recurrence of the defect.³

The frequency of gene mutations known to be essential for cardiac development, mostly encoding transcription factors, signaling molecules or structural proteins, is generally low (around 2-5%) in isolated CHD.

More recently, several studies have shown that subchromosomal changes (inherited and de novo) in genome structure, known as CNV, may be present in up to 10% of children with non-syndromic CHD.^4-6

Moreover, genome?wide and high?throughput sequencing technologies have demonstrated an excess of de novo point mutations in individuals with severe CHD and identified multiple new candidate genes.^7,8

Interestingly, pathogenic de novo variants typically occur in key development genes encoding proteins relevant for chromatin biology,⁷ suggesting that epigenetic modifications are probably relevant in the pathogenesis of CHD.

Based on a recent large study using whole-exome sequencing in family trios, de novo mutations seem to account for ~3% of isolated CHD and ~28% in patients with CHD accompanied by neurodevelopmental and/or extra-cardiac congenital anomalies.⁹

Hence, these studies show that there is a shared genetic etiology between CHD and neurodevelopmental disorders (autism or intellectual disabilities), mainly involving chromatin modifiers genes.^8,9

Additionally, the identification of rare inherited variants of a known CHD gene in non-syndromic patients, also supports an oligogenic complex mode of inheritance.^9,10

However, establishing the biological and clinical significance of a specific variant is probably the most challenging task in the era of massively parallel sequencing technology.

Consequently, Authors nicely discuss experimental models including genetically manipulated animals and human induced pluripotent stem-cell-based approaches as powerful strategy to verify the effect of suspected candidate disease genes or sequence variants on cardiac development and function.² These models have also the potential to develop therapeutic strategies for genetic cardiac disorder.

Furthermore, it is widely thought that the etiology of most non-syndromic CHD may arise from a complex combination of genetic and environmental factors that interfere with cardiogenesis process. However, in the AHA statement, less attention has been given to the combined role of genetic and environmental factors in CHD risk, even though there is growing evidence that this association may play a key role.

For instance, there is increasing evidence that common genetic variants in xenobiotic detoxification enzymes may modify the association of parental exposure with CHD,^11-17 likely by increasing the exposure of germ cells and embryonic tissue to teratogens and environmental toxicants.

We can speculate that environmental toxicants may create de novo DNA mutations and chromosomal anomalies or alter the epigenome, deeply impacting on the cardiac development and fetal programming.

In the near future, large-scale studies should be designed to explore gene-environmental interactions that may contribute to CHD as well to identify the underlying molecular mechanisms of these interactions. The use of experimental models offers the opportunity to define the mechanistic bases by which genome and environmental factors may affect the fetal cardiac development and differentiation. It is, then, expected that such studies should ultimately facilitate the prevention of CHD and reduce the occurrence of congenital malformations in the future generations.

In summary, the writing group should be congratulated on a comprehensive review of the current knowledge on the genetic basis of congenital heart diseases, the available molecular diagnostic techniques and their application in clinical care. This AHA Scientific Statement will be a useful reference and vademecum for both scientists and clinicians.