Familial occurrence of congenital heart disease

In the Baltimore Washington Infant Study (BWIS) there was a two-fold excess of familial congenital heart disease in the total group of cases in comparison to controls. However there was considerable variation between the anatomic types of the cardiac anomalies. The family history of congenital cardiac disease was statistically associated with 11 of the 18 diagnostic subgroups. This association was present for patients with mild as well as for patients with severe cardiac defects. Additionally there was evidence of a complex etiology since the family history was only one of several potential risk factors.

The BWIS provided a unique opportunity to evaluate the concordance of sibling malformations by the enrollment over the 9-year study period of a second affected child. Among 20 such sibling pairs there was high concordance of the cardiac defects and non-cardiac defects. Genes known to be associated with cardiac abnormalities appeared in the infants and their families.

There was a single family with transmission of an atrial septal defect across three generations with a conduction defect in the older siblings and adults. This represents a well known special type of atrial septal defect which was recently explained by a mutation in a transcription factor which controls early cardiac development (Schott,1998). It is now known that the same malformationmay result from mutations in different genes and that various forms of an anomaly may represent different manifestations of the same gene. The BWIS found this to be true for the various forms of left heart obstruction that were present in relatives of infants with hypoplastic left heart syndrome, coarctation of the aorta or aortic valve abnormalities. Such genetic liability was also evident among cases of atrioventricular septal defects among whom 3 infants with Down syndrome had families in which a partial form of the defect was present: 2 in mothers and one in a sister (Ferencz, 1989).

Similarly in infants with ventricular septal defect the familial expression of congenital heart disease included severe anomalies of the outflow tract of the heart such as tetralogy of Fallot, transposition of the great vessels or common arterial trunk.

Chromosomal Abnormalities

  • Numerical Excesses or Deficiencies
    Major genetic defects such as chromosomal abnormalities were recognized as a causal association with congenital heart disease 50 years ago with the identification of numerical excesses or deficiencies. Trisomy 21, which is responsible for Down syndrome, is characteristically associated with an atrioventricular septal defect as well as other cardiac abnormalities. The same is true for trisomy18. Absence of the Y chromosome, causes Turner’s syndrome with coarctation and other left-sided heart anomalies.

    In Baltimore Washington Infant Study (BWIS), 12 % of the cases had a chromosome anomaly. There was a distinctive distribution of cardiac diagnoses in the three major types of trisomy: atrioventricular septal defect was present in 59% of trisomy 21 cases, 24% of trisomy 18 cases, and none of the trisomy 13 cases. In contrast outflow tract defects, made up 50% of Trisomy13-15 cases, 18% of trisomy 18 cases, and only 6% of trisomy 21 cases.These findings suggest specific developmental relationships.

  • Structural Abnormalities
    Since the BWIS was completed there has been a rapid expansion of information on deletions within chromosomes associated with specific cardiac and non-cardiac defects. This is a rapidly advancing field of knowledge (Goldmuntz, 2001). Structural abnormalities of chromosomes, such as deletions of a small segment, as of chromosome 22q11, occur among patients with tetralogy of Fallot and persistent arterial trunk. A common arterial trunk in association with thymus and facial abnormalities constitutes the DiGeorge syndrome, which is also found with other forms of congenital heart disease including aortic arch defects (Goldmuntz, 2001, McElhinney, 2001). Deletions of chromosome 22 have also been found in families in which both congenital heart disease and neural tube defects have occurred (Kousseff Syndrome) (Forrester, 2002).

Genetic Complexes

Embryologic disturbances that may be due to gene mutations may lead to congenital heart disease and also to abnormalities in other organ systems. Combinations of these abnormalities define specific entities that may be expressed in various members of the family. Recognition of even mild abnormalities may indicate an increased genetic risk for the offspring of adults with congenital heart disease.

Complexes of multisystem malformations are of a great variety.In the Baltimore-Washington Infant Study about 5% of the patients were so diagnosed. In the Study’s report, Dr. I.W. Lurie discussed the various syndromes. His table of 55 syndromes that occurred in the study shows the combinations of abnormalities, frequency of associated heart disease, presumed etiology and references to the Birth Defects Encyclopedia. (Lurie, 1997)

Common associations included the Noonan and the Holt-Oram syndrome as well as the Williams syndrome, which has now been demonstrated to represent a microdeletion of chromosome 7q11. With advancing knowledge in chromosome structure other syndromes are likely to be more precisely identified.

Heritable coagulation disorders

An important finding of the Baltimore Washington Infant Study (BWIS) was the recognition that familial clotting abnormalities, such as hemophilia and Von Willebrand’s disease were confined to case families and did not occur in controls. This suggested the hypothesis that coagulation defects may play a role in cardiac development. (Ferencz 1984) This proposal was further evaluated coincidentally with the dramatic advances in Vascular Biology which followed the successful culture of endothelial cells and the determination of their manifold biologic functions. (Ferencz, 2000) The hypothesis has found support in the work of cell biologists (English, 2002) and in clinical observations (DiGiglio 2001) of severe congenital heart disease, notably transposition of the great arteries, in hemophiliac families. (Ferencz, 2002)

Current advances in molecular genetics explore the mechanisms of protein formation and cellular signals with an explosive extension of our understanding of heredity and development. These will become the new horizons representing the “closed doors” referred to by Nora.

“Although we have opened many doors to learn about the causes of congenital heart disease, we have found that the doors lead to new corridors flanked by many more doors”

James J Nora, 1993 Am Heart Journal :125: 409.

Selected Web Resources

  • GeneTests
    By providing current, authoritative information on genetic testing and its use in diagnosis, management, and genetic counseling, GeneTests promotes the appropriate use of genetic services in patient care and personal decision making.It is funded by the National Institutes of Health.
  • HuGENet
    Human Genome Epidemiology Network from the CDC is a global collaboration of individuals and organizations committed to the assessment of the impact of human genome variation on population health and how genetic information can be used to improve health and prevent disease.
  • National Society of Genetic Counselors
    The mission of the society is to promote the genetic counseling profession as a recognized and integral part of health care delivery, education, research and public policy.

Selected References