Genetics of Structural Congenital Heart Defects
Pp. 3-25 (23)
Maria Cristina Digilio, Bruno Dallapiccola and Bruno Marino
Epidemiological studies, clinical observations and recent advances in
molecular genetics are shedding increasing light on the genetic origin of congenital
heart disease (CHD). Chromosomal anomalies, Mendelian syndromes or associations
account for nearly 30% of all congenital cardiac malformations. These developmental
anomalies may be part of well-defined syndromes due to chromosomal or submicroscopic
genomic anomalies or may be non-syndromic as a consequence of still
unidentified genes with sporadic occurrence in families. This paper summarizes the
available findings from literature on the inference of genetics on cardiac development
by classifying the congenital heart diseases as cono-truncal defects, atrio-ventricular
canal and septal defects, right-sided obstruction and left-sided obstruction.
Cono-truncal defects represent an anatomically heterogeneous group of CHDs affecting
the outflow tract of the ventricles and the arterial pole of the heart. The most common
malformations of this group are tetralogy of Fallot, pulmonary atresia with ventricular
septal defect, truncus arteriosus and interrupted aortic arch. These CHDs are associated
with genetic syndromes in 25-40% of cases and even in non-syndromic forms show a
high incidence of mono-genic abnormalities.
Atrio-ventricular canal is a complex malformation due to abnormal septation of the
“crux cordis” resulting in ostium primum atrial septal defect, inlet ventricular septal
defect and common atrio-ventricular valve. It is almost always associated with genetic
syndromes, being non-syndromic in only 25% of cases. However, septal defects other
than atrio-ventricular canal are rarely due to genetic syndromes, ranging from 3% to
25% of cases, yet with a high rate of segregation in some families.
Valvular or vascular-elicited right sided obstructions, are due to genetic syndromes in about
10% of cases and this association results in difficult treatment due to the ineffectiveness of
any percutaneous treatment and extent of the lesions along the pulmonary trunk.
Among left heart obstructions, supra-valvular stenosis is a well-know malformation due
to disruption of the elastin gene associated with Williams syndrome in many cases.
Conversely, aortic coarctation and other left-sided heart stenosis or hypoplastic
malformation are often non-syndromic, being associated with genetic syndromes in less
than 10% of cases.
In conclusion, improved molecular genetic technologies has led to the discovery of
several causes of syndromic and non-syndromic CHDs. Nevertheless, much work
remains in identifying in etiology of non-syndromic CHDs, since the number of genes
known to be involved is still limited.
Genetics, congenital heart disease, aortic stenosis, atrial septal defect,
atrio-ventricular canal, conotruncal defects, hypoplastic left heart syndrome,
interrupted aortic arch, pulmonary stenosis, tetralogy of Fallot, truncus arteriosus,
ventricular septal defect.
Division of Medical Genetics, Bambino Gesù Pediatric Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy