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Genetic Syndromes in Children

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Genetic syndromes and the link to heart defects in children

    Most of the heart conditions associated with the genetic disorders outlined below are treatable with surgery and/or medication. Genetic syndromes with related heart conditions include: 

    Down syndrome  

    Children with Down syndrome (also known as Trisomy 21) have an extra copy of their 21st chromosome. About half of children with Down syndrome also have a congenital heart condition –– the most common being atrial-ventricular septal defects, ventricular septal defects and atrial septal defects.  

    Marfan syndrome 

    Marfan syndrome is known as a connective tissue disorder. Connective tissue holds the cells of the body together, much like mortar holds bricks together in a building. Children with Marfan syndrome are born with a defect in the gene Fibrillin-1. This gene is involved in making connective tissue strong and flexible. Many people with Marfan syndrome have a weakening of the walls of the aorta (also called aneurysm), the main blood vessel that carries blood away from the heart to the rest of the body. If untreated, the heart valve can leak, or the aorta can tear or rupture: This is called dissection, which is a life-threatening and often fatal complication. In some cases, children with Marfan syndrome have a leaky heart valve that allows blood to leak back into the heart, which causes the heart to weaken and not pump enough blood forward.  

    Connective tissue disorders and aortopathy syndromes 

    There are several conditions similar to Marfan syndrome because they also can have aortic enlargement or an aneurysm. These include: 

    • Bicuspid aortic valve with aortopathy
    • Loeys-Dietz syndrome 
    • Vascular Ehlers Danlos syndrome 
    • Shprintzen-Goldberg syndrome 
    • ACTA2-associated multisystemic smooth muscle dysfunction syndrome 
    • Kyphoscoliotic Ehlers-Danlos syndrome 

    Noonan syndrome

    Noonan syndrome is one of several related genetic conditions known as RASopathies. These conditions are grouped together because they are all caused by changes in genes that use the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway to send signals. This pathway transmits messages from outside of a cell into the cell to tell it how to grow and develop. In addition to Noonan syndrome, other RASopathies include Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, Costello syndrome and others. RASopathies can affect a child’s heart, including a risk for certain types of congenital heart disease, such as pulmonary valve stenosis and hypertrophic cardiomyopathy. 

    Turner syndrome  

    Turner syndrome occurs when one of the two X sex chromosomes is missing or partially missing. Most individuals with Turner syndrome are female. Up to half of children born with Turner syndrome have heart problems, the most common being bicuspid aortic valve, coarctation of the aorta, partial anomalous pulmonary venous return (PAPVR), mitral valve disease and hypoplastic left heart syndrome. Girls with Turner syndrome have a lifelong risk of high blood pressure, high cholesterol and lipids, and aortic aneurysm and dissection, so ongoing heart care from childhood through adulthood is recommended. Learn about the multidisciplinary approach we take to treatment for Turner syndrome in our Turner Syndrome Clinic.

    22q11.2 deletion syndrome

    22q11.2 deletion syndrome, or 22q, is a genetic condition caused by a missing piece of chromosome 22. Historically, this syndrome has also been known as DiGeorge syndrome, velo cardio facial syndrome and Shprintzen syndrome. The majority of children with 22q are born with a heart defect, and common types include Tetralogy of Fallot, truncus arteriosus and interrupted aortic arch. It’s strongly recommended that all babies with these heart defects be tested for 22q. Children with 22q are at risk for other problems including immune system deficiency, low calcium, gastrointestinal reflux and learning differences. 

    Williams syndrome

    Williams syndrome is caused by a missing piece of chromosome 7. Children with Williams syndrome typically have distinctive facial features and a very social personality, as well as a narrowing of the large blood vessel that carries blood from the heart to the rest of the body, which can cause heart and blood vessel problems.  

    Elastin arteriopathy 

    Some individuals may not have a multi-gene deletion on chromosome 7 but have a change within the ELN gene. This can cause cardiac and vascular features similar to Williams syndrome, but it typically does not result in the full spectrum of physical, developmental and cognitive characteristics associated with the syndrome. 

    Alagille syndrome 

    Alagille syndrome is a multisystem disorder that usually impacts the heart, liver and eyes. The heart disease it can cause often involves the pulmonary arteries. Alagille syndrome is generally caused by a genetic change in one of two genes: Jagged1 or Notch 2. 

    Hereditary hemorrhagic telangiectasia (HHT)  

    Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal connections of the blood vessels, called arteriovenous malformations (AVMs), which can be present in the lungs, brain, liver or gastrointestinal tract. People with HHT often have significant nosebleeds and can have red spots on their skin, lips and tongue.   

    Tuberous sclerosis complex (TSC)  

    Tuberous sclerosis complex (TSC) involves abnormal growth of the skin, brain, heart, kidneys, eyes and lungs. At least half of patients with TSC will have benign tumors that may require surgery for removal, but the tumors often decrease in size or disappear as the child matures. 

    Congential heart disease with underlying genetic causes 

    Congenital heart disease (CHD) is the most common birth defect in humans. It is well recognized that many types of congenital heart disease can run in families, and that parents who have a child with CHD could be at risk of having this recur in another pregnancy/child. With advances in genetic testing and genomics we are starting to understand what causes CHD in some children.  This information can help parents and individuals with CHD understand their risk for recurrence, but can also allow more individualized care and present opportunities for personalized medicine. 

    These are a few examples of genes that are associated with CHD when a pathogenic variant is present: 

    • NKX2-5 
      • Can cause ASD, VSD, heart block, left ventricle noncompaction, Tetralogy of Fallot, hypoplastic left heart syndrome
    • NOTCH1
      • Can cause bicuspid aortic valve, coarctation of aorta, hypoplastic left heart syndrome
    • GATA6
      • Can cause Tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, ASD, VSD
    • DNAH5
      • Can cause heterotaxy syndrome with complex CHD 


    Many individuals with cardiac muscle disease (called cardiomyopathies) have an underlying genetic cause for their presentation. There are several types of cardiomyopathies, including: 

    • Hypertrophic cardiomyopathy 
    • Abnormally thick heart muscle (myocardium)
    • Dilated cardiomyopathy
    • Enlarged and weakened left ventricle, the heart’s primary pumping chamber
    • Restrictive cardiomyopathy
    • Rigid walls of the heart’s ventricles (lower chambers), which impairs function and results in reduced blood flow from the heart to the body
    • Noncompaction cardiomyopathy
    • Muscle tissue in the left ventricle (the heart’s main pumping chamber) doesn’t develop correctly, disrupting the ability to pump blood effectively
    • Arrhythmogenic cardiomyopathy
    • Heart muscle replaced by fatty and fibrous tissue, disrupting the heart’s electrical system and causing irregular heart rhythms
    • Genetic syndromes known to have risk for cardiomyopathy include Noonan syndrome, Barth syndrome, muscular dystrophies (e.g., Duchenne, Becker, Emery-Dreifuss, Limb Girdle, Myotonic dystrophy Friedrich’s ataxia and myofibrillar myopathy  


    Many individuals with heart arrhythmias (irregular heartbeats) have an underlying genetic cause for their condition. There are several known inherited arrhythmias, including: 

    • Long QT syndrome 
    • Catecholaminergic polymorphic ventricular tachycardia 
    • Brugada syndrome 

    Pulmonary hypertension (PH)

    Pulmonary hypertension (PH), when blood pressure from the heart to lungs is too high, is often associated with an underlying genetic cause. Therefore, we offer testing to our patients with PH who do not have a clear (non-genetic) reason for their presentation. 

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