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Toward a molecular understanding of congenital heart disease
R M Payne1, M C Johnson, J W Grant
1Department of Pediatrics, Washington University School of Medicine, St Louis, Mo.
Insights
Congenital heart disease (CHD) is often caused by single-gene defects, not just multifactorial causes. Understanding these genetic underpinnings is key to advancing cardiovascular research and treatment.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- Congenital heart disease (CHD) is a significant health concern with complex etiologies.
- Investigating the genetic mechanisms of human CHD has been historically challenging.
- The multifactorial theory alone inadequately explains the full spectrum of CHD causes.
Purpose of the Study:
- To review the incidence and importance of congenital heart disease (CHD).
- To explore the causative mechanisms and genetic basis of human CHD.
- To highlight the limitations of current etiological theories for CHD.
Main Methods:
- Examined molecular defects in vasculopathies like Marfan's and Williams' syndromes.
- Reviewed animal models of CHD, including genetic and developmental manipulations.
- Analyzed gene knockout studies of cardiac transcription factors.
- Presented evidence for genetic etiologies in human CHD, including familial studies and chromosomal abnormalities.
Main Results:
- Single-gene defects are frequently identified as causes of various CHD types, including sporadic cases.
- Molecular defects in extracellular matrix components (fibrillin, elastin) are linked to specific vascular conditions.
- Animal models demonstrate the critical role of genes in heart development and reveal single-gene causes for malformations.
- Genetic abnormalities, such as trisomy 21 and chromosome 22 deletions (CATCH-22 syndrome), are associated with multiple CHD types.
Conclusions:
- Human CHD is often caused by single-gene defects, even in sporadic instances.
- A single genetic defect can manifest as different forms of CHD.
- Elucidating the genetic basis of CHD offers insights into normal cardiovascular development.
- The same cardiac malformation can result from mutations at different genetic loci.
- Collaboration between clinical and basic scientists is essential for accelerating CHD research.
Background:
This review discusses the incidence and importance of congenital heart disease (CHD), the reasons that investigation of causative mechanisms for human CHD has been slow, and the limitations of the multifactorial theory for the etiology of CHD.
Methods And Results:
The molecular defects underlying three vasculopathies--Marfan's syndrome (fibrillin), supravalvar aortic stenosis, and Williams' syndrome (elastin)--and hereditary telangiectasia are presented to emphasize the role of microfibrils and extracellular matrix in the pathophysiology of these vascular defects. Animal models of CHD, including situs inversus, canine conotruncal malformations, and chick neural crest ablation, are examined to emphasize how such studies relate to human CHD, especially by pointing to single-gene defects for conotruncal malformations, candidate loci for situs inversus, and phenotypic variability caused by neural crest lesions. The crucial role of cardiac transcription factors in heart morphogenesis is emphasized by review of gene knockout studies of these factors, which cause fetal death secondary to heart maldevelopment. Several lines of evidence demonstrating genetic etiologies of human CHD are also presented, including the mapping of familial atrial septal defects, to prove that one anatomic type of CHD may be due to single-gene defects at different loci. Review of atrioventricular canal, both secondary to trisomy 21 and as an autosomal-dominant familial defect, reiterates this conclusion. The evidence that monosomy on chromosome 22 causes multiple types of CHD, including aortic arch and conotruncal defects as part of the CATCH-22 syndrome, is presented, with results supporting the idea that deletions at this site alone may cause 5% of surgically treated CHD.
Conclusions:
We conclude that (1) human CHD is frequently due to single-gene defects and that even sporadic defects may arise from a single-gene abnormality; (2) a common genetic defect may cause several apparently different forms of CHD; (3) elucidation of the genetic basis of CHD provides clues to normal cardiovascular developmental biology; (4) the same cardiac malformation can be caused by mutant genes at different loci; and (5) interactions of clinical investigators (cardiologists and cardiothoracic surgeons) with basic scientists should allow more rapid progress in defining the genetic basis of CHD.