Congenital Heart Disease andGenetic Heart Disease Flashcards by Graeme Miller

What are the causes of congenital heart disease?

Chromosomal (trisomies / monosomies)

Microdeletions (22q11 deletion, Williams)

Single gene (Noonan/CFC, Marfan)

CNV or SNV (Copy number variation / Single nucleotide variation)

Teratogens

Other

Multifactorial

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What does CNV stand for?

Copy number variation (CNVs)

Sections of the genome are repeated and the number of repeats in the genome varies between individuals in the human population.

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What does SNV stand for?

Single nucleotide variation

A variation in a single nucleotide without any limitations of frequency

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What are the congenital heart defects associated with Down syndrome? (trisomy 21)

Atrioventricular septal defects

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What is the main risk factor attached to bearing a child with down syndrome?

Maternal age

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What is used to determine the presence of down syndrome?

Nuchal scan - detect cardiovascular abnormalities

Increased nuchal translucency associated with pathology

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What is the percentage of fetuses/newborns with CHD have abnormalities with chromosomes?

19% of fetuses

13% of newborns

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What heart defects is Turner syndrome associated with? (45,X)

Coarctication of the aorta

(Short stature, puffy hands, gonadal dysgenesis)

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What causes neck webbing?

Excess nuchal folds

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What syndromes are associated with neck webbing?

Turner syndrome

Noonan syndrome

CFC syndrome

Leopard syndrome

Costello syndrome

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What is the effect of noonan syndrome on circulation?

Pulmonary valvular stenosis (50–60%)

Septal defects: atrial (10–25%) or ventricular (5–20%)

Hypertrophic cardiomyopathy (12–35%)

Also causes (short stature, neck webbing, cryptorchidism (he absence of one or both testes from the scrotum), characteristic face)

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What gene is responsible for noonan syndrome?

PTPN11 mutation

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What are the noonan like syndromes?

lCardio-Facio-Cutaneous (CFC)

lLeopard syndrome

lCostello syndrome

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What pathway are Leopard, Noonan, CFC and Costello syndrome all associated with?

Associated with mutations in the MAPK pathway (Mitogen activated Protein Kinase)

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What does CATCH 22 refer to?

Cardiac malformation

Abnormal facies

Thymic hypoplasia

Cleft palate

Hyperthyroidism

22q11 deletion

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What is the most common microdeletion syndrome?

22q11 deletion syndrome

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What conditions does 22q11 deletion syndrome encompass?

DiGeorge and velocardiofacial syndrome (Shprintzen)

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What are the sings/symptoms associated with DiGeorge syndrome?

Thymic hypoplasia

Hypoparathyroidism

Outflow tract cardiac malformation

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What are the signs/symptoms associated with Velocardiofacial syndrome?

lCleft palate/palatal insufficiency

lOutflow tract cardiac malformation

lCharacteristic face

lAutosomal dominant

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What percentage of 22q11 deletion syndrome is familial?

about 25%

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What is the common mental problema associated with 22q11 deletion syndrome?

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What are LRC’s and how do they predispose 22q11 to deletion and translocation?

LCR’s are highly homologous sequence elements within the eukaryotic genome.

Misalignment of LCRs during non-allelic homologous recombination (NAHR) is an important mechanism underlying the chromosomal microdeletion disorders.

(Non-allelic homologous recombination (NAHR) is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles. It usually occurs between sequences of DNA that have been previously duplicated through evolution, and therefore have low copy repeats)

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What are the heart problems associated with Williams syndrome?

Aortic stenosis (supraclavicular)

Hypercalcaemia

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What causes Williams syndrome?

Deletion of elastin on chromosome 7

Deletion of contiguous genes (deletion or duplication that removes several genes lying in close proximity to one another on the chromosome)

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List some teratogens

Alcohol Antiepileptic drugs Rubella (congenital rubella syndrome - causes heart defects among many other things) Maternal Diabetes Mellitus

Who is the biggest factor on whether or not you will get a congenital heart disease?

Mother - if mother is affected the risk is much higher than sibling or father

What is VSD associated with?

Folate deficiency

What are the specific types of genetic cardiac disease?

Cardiovascular connective tissue disease Familial Arrhythmias Familial Cardiomyopathy

What are the typical features of Marfan's syndrome?

Tall stature Pectus carinatum Arachnodactyly (long fingers) Lens subluxation Aortic dilation/dissection A high, arched palate and crowded teeth. Heart murmurs. Extreme nearsightedness. An abnormally curved spine. Flat feet.

What is the inheritance pattern associated with Marfan syndrome?

Autosomal dominant

What gene is responsible for Marfan syndrome?

**Fibrillin 1 gene** Chromosome 15q21 TGFbR 2 (and TGFbR 1) chromosome 3p22 (9q33)

What is the clinical diagnosis of marfan syndrome?

Ghent criteria - 2 system findings must be positive

What are the skeletal features of marfans syndrome?

Arm span exceeds height Scoliosis/kyphosis Pectus deformity Thumb and wrist Foot/ankle Reduced elbow extension

What are other systemic features of marfans?

Most features are assessed clinically: When should additional tests be done?

Echocardiography mandatory in every case Undertake MRI and/or pelvic X-ray where diagnosis would change if positive MRI used to detect dural ectasia (Dural ectasia is widening or ballooning of the dural sac surrounding the spinal cord) Pelvic X-Ray for protrusio acetabuli

What percentage of marfan patients have a detectable fibrillin 1 mutation?

70-90% of Marfan patients

What is the relationship between fibrillin and TGF beta

Incorporation of fibrillin into microfibrils results in proteolytic release of TGF beta ## Footnote TGFb signalling affects cell proliferation, differentiation and apoptosis TGFb antibodies, or the TGFb antagonist Losartan rescue the Marfan phenotype in Fibrillin deficient mice.

What are the marfan like syndromes?

Loeys-Dietz Syndrome Marfan Syndrome type 2 Familial Thoracic Aortic Aneurysms MASS phenotype

What is the risk assoicated with a aortic root dilitation? (feature of marfans)

The primary risk that a dilation presents is that the aorta can stretch the valve, weakening or even tearing the heart.

What is the investigation used to monitor marfans syndrome?

Echocardiogram Aortic root is frequently monitored during pregnancy if the diameter exceeds 4 cm.

When is there a need for prophylactic aortic surgery?

When the sinus of the vasalva exceeds 5.5 cm or 5% growth per year (2 mm in adults)

What are the drugs given to marfan syndrome people?

Beta blockers Angiotensin II Receptor Blockers

What is a common cause of sudden unexpected death?

Arrythmia Channelopathy present - majority of these have a long QT

What is responsible for ion channelopathies?

Genes

When is arrythmia brought on whith the KCNQ1 mutation? And what is the T wave pattern on a 12 lead ECG?

Excersize, particularly swimming - normal / broad T-wave pattern

When is arrythmia brought on when the KCNH2 mutation is present? Amd what is the T wave pattern on a 12 lead ECG like?

Noise/arousal e.g telephone ring, alarm clock ECG is: Notched

When is arythmia brought on with the SCN5A mutation? And what is the T wave pattern?

Sleep/bradycardia Biphasic T waves

What are the genes KCNQ1, KCNH2 and SCN5A responsible for?

Ion channels in the heart, however they are responsible for long QT ion channelopathies

Why is genotyping useful for Long QT channelopathies?

Gene carriers are susceptible to arrythmias Can indicate prognosis Helps identify the correct treatment

What is possible treatment for long QT?

Beta blockers

What does QTc stand for?

QT interval

What is Brugada syndrome?

Ion channel disorder Defective sodium channel Autosomal dominant Normally not lethal Causes ST elevation in most patients Can cause diziness and fainting Also associated with SCN5A

What is treatement for Brugada syndrome?

Defib

Give an example of familial cardiomyopathy

Hypertrophic cardiomyopathy

What is the presence of hypertrophic cardiomyopathy?

1/500

What is hypertrophic cardiomyopathy?

A disease in which the heart muscle (myocardium) becomes abnormally thickHypertrophic cardiomyopathy usually is inherited. It's caused by a change in some of the genes in heart muscle proteins. HCM also can develop over time because of high blood pressure or aging. Diseases such as diabetes or thyroid disease can cause hypertrophic cardiomyopathy

What genes are often mutated in hypertrophic cardiomyopathy?

Mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators.

What is ARVC?

ARVC is a disorder of the myocardium, which is the muscular wall of the heart. This condition causes part of the myocardium to break down over time, increasing the risk of an abnormal heartbeat (arrhythmia) and sudden death. The walls of the ventricle become thin and stretched. Eventually there is weakening of both the left and right ventricle. ARVC can also cause abnormal heart rhythms, because your heart’s normal electrical impulses are disrupted as they pass through areas of damaged and scarred muscle cells.

What are the common findings in an ARVC echocardiogram?

Dilated right ventricle

What is the ECG findings for ARVC?

Effort induced polymorphic tachycardia (LBBB pattern) T wave inversion V2-3 on resting ECG

What inheritance pattern does ARVC follow?

Autosomal dominant

What genes are responsible for ARVC?

What is dilated cardiomyopathy?

Dilated cardiomyopathy (DCM) is a condition in which the heart's ability to pump blood is decreased because the heart's main pumping chamber, the left ventricle, is enlarged and weakened. In some cases, it prevents the heart from relaxing and filling with blood as it should.

What are the relevant genetic tests associated with dilated cardiomyopathy?

LMNA, SCN5A, dystrophin and the sarcomere genes

What are the common symptoms associated with dilated cardiomyopathy?

Palpitations Light-headedness Fainting Breathlessness Abnormal heart rhythms Swollen ankles or legs Swelling in the abdomen Risk of sudden death on exertion

What conditions should be excluded when determining the cause of the symptoms? ## Footnote (Palpitations Light-headedness Fainting Breathlessness Abnormal heart rhythms Swollen ankles or legs Swelling in the abdomen Risk of sudden death on exertion)

Ischaemic heart disease (angiography) Hypertension Skeletal muscle disease (neurology/genetics evaluation, CPK) Alcohol abuse (history and biochemical evidence) Exposure to cardiotoxic drugs (history) Haemochromatosis (ferritin/genotyping)

What is cascade screening?

When an abnormal ECG is detected, 3 generation family history is collected, ECG's for first degree relatives, search for mutations in genome of original patient. (All the way trying to determine potential familial inheritance?)

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