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CONGENITAL HEART DEFECTS AND ASSOCIATED GENETIC DISORDERS
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The complexity of cardiac embryology suggests that multiple genes are involved in directing
development of the heart.
Mutations in control and structural genes appear to result in the great variety of congenital
malformations of the heart.
ANEUPLOIDY (abnormal number of chromosomes)
****Down Syndrome: Trisomy 21
Atrial/ventricular septal defects (AVSD)
40% of Down Syndrome patients have heart defect
Half of these are AVSD
Edwards Syndrome
Trisomy 18
Ventricular septal defects (VSDs), AVSDs, double
outlet right ventricles, and hypoplastic hearts
Patau Syndrome
Trisomy 13
Atrial and septal defects; Disturbance of the
cardiac position has also been reported and
includes detrocardia; these findings support the
role of chromosome 13 genes in laterality of
development.
Turner Syndrome
45,X
hypoplastic left heart; aortic coarctation; bicusupid
aortic valves and mitral valve prolapse.
Atrioventricular septal defect (AVSD) characterized by a deficiency of the atrioventricular septum of the
heart which is a septum of the heart between the right atrium (RA) and the left ventricle (LV)
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results in formation of a hole in the center of the heart and a large single valve between the upper and
lower heart chambers.
holes allow blood from the heart's left side to enter the heart's right side
heart has to work much harder than normal to pump enough blood out to the body
Genes associated with AVSD:
CRELD1
CRELD2
Gene family thought to be involved in cell
adhesion
Not related to trisomy
GATA4
essential for cardiac development
Bone Morphogenic protein-4
Deficiency results in abnormal development of
cardiomyocytes
Type VI Collagen
Chromosome 21 associated
Genes fall within the heart defect critical region on
chromosome 21
CHROMOSOME DELETION SYNDROMES
William’s Syndrome
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characteristic appearance with mild short
stature, a full lower lip and sloping shoulders
characterized as a “cocktail party manner”
Supravalvular aortic stenosis (SVAS) – instead of
having 3 leaflets on heart valves, you only have 2 –
valves did not form properly due to lack of elastin
Haploinsufficiency of 7q11 leads to loss of one
copy of elastin gene  key causative factor for
SVAS
DiGeorge Syndrome
one of the most common congenital defects
Catch 22
• Cardiac outflow tract anomalies
• Abnormal faces
• Thymic hypoplasia
• Cleft palate
• Hypocalcemia
• Microdeletion of chromosome 22
defective cranial neural crest function, especially
that associated with those neural crest cells
populating aortic arches 3 and 4
multigene, heterozygous, interstitial chromosomal
deletion (approximately 30 genes are deleted) 
DiGeorge Critical Region
TBX1 mutations are associated with heart defects
(involved with a growth factor)
CARDIAC HYPERTROPHY  disproportionate hypertrophy of the left ventricle and occasionally also of
the right ventricle
Major Myopathies: (are others but not listed)
Hypertrophic cardiomyopathy (HCM)
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two types of cardiac hypertrophy: pathological and physiological
Pathological  Occurs under conditions such as hypertension or genetic conditions affecting
myofibril proteins.
• hypertension, mutations – will get fibrosis!! Can get heart failure
Genetically mediated: broader and often subtle phenotype which may be a consequence of
incomplete gene penetrance and variable disease expression
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most common inheritance pattern is autosomal dominant with variable penetrance and
expression.
• Mutations in four contractile protein gene:
• b-cardiac myosin
• troponin T
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a-tropomyosin
• myosin binding protein.
• Mutations that produce a change in charge are considered to have a major impact on
protein stability
Clinical Features
• Patients may be entirely asymptomatic or affected by varying degrees of dyspnea, chest
pain, palpitation, or syncope.
• Rhythm disturbances include atrial fibrillation, supraventricular tachycardia, and ventricular
tachycardia.
• Clinical Risk Stratification: In adults, a family history of sudden death and a personal
history of syncope or documented non-sustained ventricular tachycardia are predictors of
adverse prognosis. In children, there are few reliable markers of poor prognosis
Long QT interval
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Long QT syndrome (LQTS) is an abnormality of cardiac rhythm, characterized by delayed ventricular
repolarization which is seen as a prolonged QT interval
The arrhythmia results in recurrent spontaneous syncope (loss of consciousness), seizures and
sometimes, sudden cardiac death.
LTQ syndrome is caused by repolarization defects in cardiac cells
LTQ syndromes are heterogeneous group of disorders known as channelopathies because they are
caused by defects in cardiac ion channels
The most common is autosomal dominant (AD) Romano-Ward Syndrome
• syncope due to cardiac arrhythmia is the most frequent symptom
LTQ triggers are typically adrenergic and include exercise and sudden emotions
Ehlers Danlos Syndrome
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group of generalized connective tissue disorders
result from deficiency of collagen-processing enzymes (collagen 1,3, 5 affected)
most clinically important mutations are found in the gene for type III collagen
Collagen III is an important component of the arteries  potentially lethal vascular problems can
occur
Vascular Ecchymotic (Type IV)
• Only type associated with reduced life expectancy
• ****Medium-sized artery spontaneous rupture – can lead to early death
• Defect in Type III collagen – it is not as strong
• Chromosome 2q31 location
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Diagnosis in Ehlers Danlos IV
• Major Criteria
• Thin, translucent skin
• Arterial/intestinal fragility or rupture;
• Extensive bruising
• Characteristic facial appearance
• Thin lips & philtrum, thin nose, small chin, large eyes
****Weakness of Type III Collagen leads to aneurysm and dissection commonly in visceral
arteries and iliaofemoral arteries.
Marfan Syndrome
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Fibrillin is defective  leads to poor anchoring of collagen
Signs: disproportionately long limbs (arachnodactyly); Joint hypermobility
Cardiovascular Sequelae in Marfan’s Syndrome
• Tissues don’t adhere well
• Normal forces across arterial wall result in shear  Leads to Aortic dissection
• Collagen sheets are not anchored well and do not undergo effective repair
• Results in degeneration of heart valves (particularly aorta and mitral) that lead to
murmurs & insufficiency
Major criteria
• Dilatation of the ascending aorta w/ or w/o aortic regurgitation & involving at least the
sinuses of Valsalva; or
• Dissection of the ascending aorta
Minor criteria
• Mitral valve prolapse w/ or w/o mitral valve regurgitation
• Mitral Valve Prolapse – Leaflets are stretched and flop back into the left atrium with
each heart beat – blood does not move out effectively
• Dilatation of the main pulmonary artery in a patient  40 years old in the absence of
valvular, peripheral pulmonic stenosis or other obvious cause
• Calcification of the mitral annulus  40 years
• Dilatation or dissection of the descending thoracic or abdominal aorta  50 years
• For cardiovascular system involvement: (1) major criterion or only (1) one of the minor
criteria must be present.