Genetic syndromes linked to heart diseases.

Congenital heart disease

22q11.2 deletion syndrome (Digeorge syndrome, velocadiofacial syndrome)

Clinical features: Facial dysmorphia, palate and speech abnormalities, thymic and parathyroid hypoplasia, hypocalcemia, immunodeficiency, neurodevelopmental and psychiatric disorders.

Percentage of affected patients with congenital heart disease: 60-80%

Common cardiac findings: Interrupted aortic arch type B, other aortic arch abnormalities, truncus arteriosus, tetralogy of Fallot, ventricular septal defect/pulmonary atresia

Down syndrome

Genetic abnormality: Trisomy 21

Clinical features: Facial dysmorphia, developmental disability, atlantoaxial instability, obstructive sleep apnea, craniofacial abnormalities

Percentage of affected patients with congenital heart disease: 40%-50%

Common cardiac findings: Atrial septal defect, ventricular septal defect, atrioventricular septal defect, tetralogy of Fallot

Holt–Oram syndrome

Genetic abnormality: TBX5

Clinical features: Upper-limb skeletal abnormalities, conduction abnormalities

Percentage of affected patients with congenital heart disease: 75%

Common cardiac findings: Atrial septal defect, ventricular septal defect, valvular disease (mitral valve prolapse, pulmonary stenosis)

Klinefelter syndrome

Genetic abnormality: 47,XXY

Clinical features: Tall stature, hypoplastic testes, delayed puberty and developmental disability

Percentage of affected patients with congenital heart disease: 50%

Common cardiac findings: Patent ductus arteriosus, atrial septal defect, mitral valve prolapse

Noonan syndrome

Genetic abnormality: PTPN11, KRAS, SOS1, RAF1, NRAS, BRAF, MAP2K1

Clinical features: Facial anomalies, webbed neck, chest deformity, lymphatic abnormalities, bleeding abnormalities

Percentage of affected patients with congenital heart disease: 80%

Common cardiac findings: Pulmonary stenosis, atrial septal defect, hypertrophic cardiomyopathy, atrioventricular septal defect

Turner syndrome

Genetic abnormality: 45,X

Clinical features: Short stature, webbed neck, lymphedema, primary amenorrhea

Percentage of affected patients with congenital heart disease: 30%

Common cardiac findings: Bicuspid aortic valve, coarctation of the aorta, aortopathies, partial anomalous pulmonary venous connection, atherosclerosis risk

Williams syndrome

Genetic abnormality: 7q11.23 deletion

Clinical features: “Elfin” facial features, social personality, hearing loss, developmental delay, infantile hypercalcemia

Percentage of affected patients with congenital heart disease: 50-80%

Common cardiac findings: Supravalvar aortic stenosis, branch pulmonary artery stenosis, supravalvar
pulmonary stenosis, coronary ostial stenosis, QTc prolongation, mid-aortic narrowing syndrome

Alagille syndrome

Genetic abnormality: JAG1

Clinical features: Facial dysmorphism, hepatic dysfunction (chronic cholestasis, elevated liver
enzymes, biliary atresia, hypercholesterolemia, or liver failure), neurovascular accidents, renal anomalies (renal artery stenosis, hypertension, renal tubular acidosis, uteropelvic obstruction, small, hyperechoic kidneys)

Percentage of affected patients with congenital heart disease: 70-75%

Common cardiac findings: Two-thirds with peripheral or branch pulmonary artery stenosis or other arterial narrowing (coarctation of the aorta, renal artery stenosis, middle cerebral artery, Moyamoya); also can have tetralogy of Fallot, aortic stenosis, septal defects, mid-aortic narrowing syndrome

Heterotaxy syndrome

Genetic abnormality: ZIC3, SHROOM3, GRK5, ANKS3, NODAL, CFC1, LEFTY2, GDF1, SMAD2, ACVR2B

Clinical features: Situs abnormalities, ciliary dysfunction, functional asplenia, conduction abnormalities, biliary atresia

Percentage of affected patients with congenital heart disease: 50%-95%

Common cardiac findings: Atrioventricular septal defect (balanced, unbalanced), malposed great vessels, interrupted inferior vena cava, bilateral superior vena cava, atrial isomerism

Reference

Stout KK, Daniels CJ, Aboulhosn JA, Bozkurt B, Broberg CS, Colman JM, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019 Apr 2;73(12):e81–192. doi:10.1016/j.jacc.2018.08.1029