heart disease

The Genetic Causes of Congenital Heart Disease

Editor’s Note: This article is a Consultant360 exclusive sidebar to “A Review of Infective Endocarditis Associated With Congenital Heart Disease,” by Evan J. Leonard, MS, MMS, PA-C; Brandon E. Kuebler, MD; Martin M. Zenni, MD; and Christopher B. Scuderi, DO, from the November 2017 issue of Consultant. Click here to access the main article.

Author: 
Evan J. Leonard, MS, MMS, PA-C

Understanding the genetic causes of malformations of the heart is increasing in importance as a result of the growing role of genetic testing. Moreover, the increasing number of persons surviving longer with congenital heart disease (CHD) makes it important to bear these genetic pathologies in mind when considering possible comorbidities of CHD, such as IE. The accompanying Table lists a number of syndromes associated with CHD.1-3

Congenital Heart Disease

During the third and eighth weeks of embryogenesis, the major groundwork of cardiogenesis occurs. This is the critical period during which genetic mechanisms can fail or become interrupted, leading to the majority of cases of CHD. Among the numerous potential causes of this failure or interruption are genetics, teratogens (eg, lithium, retinoids), infections of pregnancy (eg, congenital rubella), maternal diabetes, radiation, and idiopathic or spontaneous causes. Most cases of CHD are idiopathic, with no clinically identifiable genetic abnormality.4

During early cardiogenesis, the Notch signaling pathway is primarily responsible for the prepatterning of cardiac mesoderm.5 Alterations in the Notch pathway can affect bone morphogenetic protein-2 in cardiac myocytes, resulting in atrioventricular canal defect.5 Notch proteins 1 and 4 via HEY1, HEY2, and HEYL regulate aortic arch development.5 It has been postulated that this pathway may be interrupted in the case of coarctation of the aorta. Bicuspid aortic valve disease is the result of a disruption, usually a single-point mutation, in the epithelial-to-mesenchymal transformation, which is controlled by NOTCH1.5

Alagille syndrome, or arteriohepatic dysplasia, is an example of an autosomal dominant mutation in the Notch 2 signaling pathway, resulting in either pulmonary stenosis or tetralogy of Fallot (TOF).5

Other major genetic pathologies involve NKX2-5, which is malformed in many cardiogenetic diseases and has been proven to be a key cause of ventricular septal defects when mutated.6 It is located on 5q35, which regulates several cardiac genes. NKX2-5 mutation is one of 3 causes of familial atrial septal defect, the other 2 being GATA4 on the short arm of chromosome 8 and MYH6 on the long arm of chromosome 14.

Heterotaxy syndrome may cause septal defects or pulmonary stenosis. Patients with it may also have asplenia and thus are more susceptible to encapsulate bacteria.3 DiGeorge syndrome (22q11.2 deletion syndrome) may feature interrupted aortic arch, truncus arteriosus, or TOF.1

Familial patent ductus arteriosus (PDA), which typically occurs in Char syndrome, is found on chromosome 6 with mutations in TFAP2B, a neural crest cell gene. Patent ductus arteriosus typically manifests spontaneously, but in Char syndrome, it is associated with facial and carpal dysmorphism. Holt-Oram syndrome (hand-heart syndrome) is a similar condition that presents with defects in the carpal bones and CHD, typically atrial septal defect (ASD) or ventricular septal defect (VSD), but sometimes TOF, PDA, or mitral valve defects.2

CHD often presents as a manifestation of a collagen disease such as Marfan syndrome or Ehlers-Danlos syndrome (EDS). Marfan syndrome occurs in 1 of 5000 live births and is an autosomal-dominant disease located on the long arm of chromosome 15, which contains FBN1 encoding for fibrillin, the major component of extracellular microfibrils in elastic and nonelastic connective tissues.2 This results in severe laxity of connective tissue, possibly affecting the heart in the form of dilatation of the aortic root, aortic dissection, and aortic and mitral valve regurgitation.2 EDS is a collagenous disease that manifests in several forms, the most serious of which is type IV; it is caused by mutations of COL3A1 on 2q31, encoding for type III procollagen. The consequence of this malformation is extensive, but cardiac involvement most commonly comprises TOF, ASD, valvular abnormalities, or great vessel aneurysms.2

Most of the pathologies discussed here are monogenic; however, many polygenic diseases cause CHD. Among them are trisomy 13 (Patau syndrome), which occurs 1 in 5000 to 1 in 20,000 births and presents with several cardiac defects; trisomy 18 (Edwards syndrome), which occurs 1 in 8000 births and presents with VSD; and trisomy 21 (Down syndrome), a chromosomal aberration that frequently presents with complete atrioventricular canal, VSD, TOF, or ASD.7

These congenital malformations of the heart are associated with disruption of the endocardial anatomy, predisposing persons with them to IE. 

Evan J. Leonard, MS, MMS, PA-C, is an assistant professor at the Nova Southeastern University Physician Assistant Program in Jacksonville, Florida.

References:

  1. Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev Disabil Res Rev. 2008;14(1):35-42.
  2. Marian AJ, Brugada R, Roberts R. Cardiovascular diseases caused by genetic abnormalities. In: Fuster V, Walsh RA, Harrington RA, et al, eds. Hurst’s the Heart. Vol 1. 13th ed. New York, NY: McGraw-Hill; 2011:chap 82.
  3. Mishra S. Cardiac and non-cardiac abnormalities in heterotaxy syndrome. Indian J Pediatr. 2015;82(12):1135-1146.
  4. Mitchell RN. Heart. In: Kumar V, Abbas AK, Aster JC, eds. Robbins Basic Pathology. 10th ed. Philadelphia, PA: Elsevier; 2017:chap 11.
  5. Zhou XL, Liu JC. Role of Notch signaling in the mammalian heart. Braz J Med Biol Res. 2014;47(1):1-10.
  6. Qin X, Xing Q, Ma L, et al. Genetic analysis of an enhancer of the NKX2-5 gene in ventricular septal defects. Gene. 2012;508(1):106-109.
  7. Brown DW, Fulton DR. Congenital heart disease in children and adolescents. In: Fuster V, Walsh RA, Harrington RA, et al, eds. Hurst’s the Heart. Vol 1. 13th ed. New York, NY: McGraw-Hill; 2011:chap 83.