Genetics of Cardiovascular Disease Flashcards by Chloe Mackle

What are the causes of congenital heart defects?

Copy number variation e.g. trisomy 21, 22q11 deletion
Single nucleotide variation - Mendelian disorders e.g. Marfans
Multifactorial - isolated CHD
Uncertain
Teratogens e.g. rubella, sodium valproate

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Down syndrome is caused by trisomy of what chromosome?

Trisomy 21

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What percentage of Down syndrome is due to maternal non-dysfunction, and what is this associated with?

95% maternal non-dysjunction

Associated with maternal age

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What percentage of Down syndrome is due to translocation and what percentage is due to mosaic abnormalities?

3% translocation

2% mosaic

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What percentage of babies with Down syndrome have atrioventricular septal defects?

15%

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What congenital abnormalities might a baby with Down syndrome have?

Atrioventricular septal defect
Duodenal atresia
Nuchal translucency

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Is chromosome abnormality more common in foetuses with congenital heart disease or in newborns with congenital heart disease?

More common in foetuses with congenital heart disease - 19% of foetuses with CHD will have abnormal chromosomes whereas only 13% of newborns with CHD will have abnormal chromosomes

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What is Turner syndrome?

Condition where a female has only one normal X sex chromosome rather than 2 - 45X

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What percentage of Turner syndrome is caused by a mosaic mutation?

30%

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Turner syndrome is present in how many live births?

1/3000

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What cardiovascular abnormality is seen in Turner syndrome?

Coarctation of the aorta

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What are the features of Turner syndrome?

Short stature
Gonadal dysgenesis
Puffy hands
Neck webbing

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What are the single gene disorder causes of neck webbing?

Turner syndrome
Noonan syndrome
CFC syndrome
Leopard syndrome
Costello syndrome

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What is the gene affected in Noonan syndrome?

PTPN11 gene

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What are the features of Noonan syndrome?

Short stature
Neck webbing
Cryptorchidism
Characteristic face

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What cardiovascular abnormality is associated with Noonan syndrome?

Pulmonary stenosis

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What are the features of cardio-facio-cutaneous syndrome?

Noonan-like appearance
Ectodermal problems
Developmental delay

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What are the features of Leopard syndrome?

Noonan-like appearance
Multiple lentigines
Deafness

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What are the features of Costello syndrome?

Noonan-like appearance 
Thickened skin folds
Susceptibility to warts
Cardiomyopathy 
Cancer risk in later life

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What are the CATCH 22 features of 22q11 deletion syndrome)

CATCH 22

C - cardiac malformation
A - abnormal facies
T - thymic hypoplasia
C - cleft palate
H - hypoparathyroidism
22 - 22q11 deletion

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What are the other features of 22q11 deletion syndrome?

Renal and psychiatric problems
Speech delay
Palatal dysfunction
Very variable disorder

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When should genetic testing be done for 22q11 deletion syndrome?

If 2 or more clinical features are present

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What percentage of 22q11 deletion syndrome is familial?

25%

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What is the frequency of 22q11 syndrome in unselected CHD?

Around 1-2%

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What is the relationship between psychiatric disorders and 22q11 syndrome?

Linked with schizophrenia, depression and bipolar affective disorder

What syndromes are encompassed by 22q11 syndrome?

DiGeorge and Shprintzen (velocardiofacial)

What are the features of DiGeorge syndrome?

Thymic hypoplasia Hypoparathyroidism Outflow tract cardiac malformation Usually sporadic

What are the features of Shprintzen syndrome?

Cleft palate/palatal insufficiency Outflow tract cardiac malformation Characteristic face Autosomal dominant

What cardiovascular abnormality is associated with Williams syndrome?

Aortic stenosis (supravalvular)

What are the features of Williams syndrome?

Hypercalcaemia 5th finger clinodactyly Characteristic face "cocktail party manner" - children will have no speech delays but conversations may not make sense/patient might not understand what you're saying

What genetic abnormalities are seen in Williams syndrome?

Deletion of elastin on chromosome 7 Deletion of contiguous genes Deletion of LIM kinase

What are the common teratogens?

``` Alcohol - foetal alcohol syndrome Illicit drugs Anti-epileptic drugs Rubella Maternal diabetes mellitus if poorly controlled ```

What are the features of foetal alcohol syndrome?

``` Intrauterine growth restriction < 10th centile Head < 10th centile Characteristic face ADHD 3-5 units per week ```

What are the features of foetal anticonvulsant syndrome?

Characteristic face Malformation patterns Developmental delays Common and specific features

What drugs might cause foetal anticonvulsant syndrome?

Valproate Phenytoin Carbamazepine

What are the cardiovascular connective tissue diseases caused by genetic abnormalities?

Marfan syndrome Loeys-Dietz Ehlers-Danlos Familial thoracic aortic aneurysm (FTAA)

What are the genetic familial arrhythmias caused by genetic abnormalities?

Long QT syndrome Brugada syndrome Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

What are the familial cardiomyopathies caused by genetic abnormalities?

Hypertrophic cardiomyopathy | Dilated cardiomyopathy

What are the genetic features of Marfan syndrome?

``` Autosomal dominant Fibrillin 1 gene Chromosome 15q21 TGF beta R2 Chromosome 3p22 ```

What are the cardiovascular features of Marfan syndrome?

Aortic dilatation/disection

What condition of the eyes is caused by Marfan syndrome?

Ectopia lentis

What features are involved in the systemic score of Marfan syndrome?

``` Skeletal Skin Respiratory Dural ectasia Mitral valve prolapse Myopia ```

What are the skeletal features of Marfan syndrome?

``` USLR and SHR Scoliosis/kyphosis Pectus deformity Thumb and wrist Foot/ankle Reduced elbow extension ```

What are the non-skeletal features of Marfan syndrome?

``` Myopia MVP Pneumothorax Dura Striae Face Protrusio acetabuli ```

What feature of the family history can be used in diagnosis of Marfan syndrome?

Unequivocally affected relative

Mutation of what gene is known to cause Marfan syndrome?

Fibrillin 1

What is needed for diagnosis using the Ghent 2010 criteria?

2 system findings must be positive

What investigations are needed in Marfan syndrome?

Echocardiography mandatory in all cases | Undertake MRI and/or pelvic x-ray where diagnosis would change if positive

What percentage of Marfan syndrome patents are affected by dural ectasia?

92%

What percentage of Marfan syndrome patients are affected by protrusion?

47%

What are the features of Loeys-Dietz syndrome?

``` Arterial dissection Tortuosity Bifid uvula/cleft palate Hypertelorism Skin and skeletal findings ```

What chromosome/gene abnormalities are known to cause familial thoracic aortic aneurysms?

``` 11q 5q 3p22 16p13 10q22-24 ```

In MASS phenotype, what does MASS stand for?

M - mitral valve prolapse A - aortic root diameter at upper limits of normal for body size S - stretch marks of skin S - skeletal conditions, similar to Marfan syndrome

What are the features of MASS phenotype?

``` Myopia Mitral valve prolapse Mild aortic dilatation Striae Minor skeletal involvement ```

In sudden unexpected death, with no obvious cause found post-mortem, what is assumed to be the cause of death?

Arrhythmic

In first degree relatives studies of patients who died of sudden unexpected death, what percentage have identifiable inherited heart disease?

40-53%

What are the features of long QT syndrome?

Syncope Seizure Death

What is long QT syndrome brought on by?

Emotion Exercise Drugs

What is seen on the ECG of a patient with long QT syndrome?

Prolonged QT interval Repolarisation anomalies Paroxysmal polymorphic VT

What are the features of Jervell Lange-Neilsen syndrome?

Same features as long QT plus congenital sensorineural deafness

What is the prevalence of hypertrophic cardiomyopathy?

1/500

When is sudden death more common in patients with hypertrophic cardiomyopathy?

If diagnosed < 14 years old, or symptomatic

What is the mortality of hypertrophic cardiomyopathy?

5. 9% per year diagnosed clinically in childhood 2. 5% per year diagnosed clinically in adult life 0. 5% per year diagnosed through screening

What are the features of arrhythmogenic right ventricular dysplasia/cardiomyopathy?

Effort induced polymorphic tachycardia Right ventricular cardiomyopathy T wave inversion V2-3 on resting ECG Disordered cell junctions

What are the cell junction genes affected by ARVC?

``` Plakophilin 2 Desmoglein 2 Desmoplakin Desmocollin Plakoglobin TMEM43 TGFB3 RYR2 ```

What percentage of familial cases of ARVC is caused by plakophilin 2 mutation?

20%

What percentage of familial cases of ARVC is caused by desmoglein 2?

12-14%

What percentage of familial cases of ARVC is caused by desmoplakin?

6-15%

What are the features of dilated cardiomyopathy?

Echocardiographic features of dilated cardiomyopathy | History of syncope or pre-syncope compatible with brady/tachy-arrhythmia, or evidence of arrhythmia on ECG

When should mitochondrial disease be considered in patients with dilated cardiomyopathy?

``` If there is: Diabetes Deafness Retinitis pigmentosa Skeletal muscle disease Growth retardation Cognitive disorder ```

What is needed in the family history of a patient with dilated cardiomyopathy?

Family history of cardiomyopathy or sudden cardiac death compatible with cardiomyopathy should be evident

What tests might be done in genetic testing for dilated cardiomyopathy?

LMNA SCN5A Dystrophin Sarcomere genes

What conditions should be excluded in dilated cardiomyopathy?

``` Ischaemic heart disease Hypertension Skeletal muscle disease Alcohol abuse Exposure to cardio toxic drugs Haemochromatosis ```

In what percentage of Marfan patients is a fibrillin 1 mutation detectable?

70-90%

What Marfan patients have a better cardiovascular prognosis?

Ghent negative cases - aortic dilatation in 40% at age 40 vs 73% of Ghent positive

When should genetic testing be done for Marfan patients?

When a positive result would change the diagnosis e.g. cases with 1 major and 1 minor criteria, or 2 major criteria

What results in the proteolytic release of TGF-beta?

Incorporation of fibrillin into microfibrils

What does TGF beta signalling affect?

Cell proliferation, differentiation and apoptosis

What genes are tested in genetic testing for long QT syndrome in Scotland?

``` KCNQ1 KCNH2 SCN5A KCNE1 KCNE2 ```

What are the advantages of genotyping?

Allow determination of prognosis Lifestyle alterations Treatment

What is the optimal management of Marfan syndrome?

At least annual clinical review Echocardiogram Beta blockers Angiotensin II receptor blockers Prophylactic aortic surgery is sinus of Valsalva exceeds 5.5cm or 5% growth per year Monitor aortic root frequently in pregnancy if diameter exceeds 4cm Slow rate of dilatation (beta blockers)

What are the advantages and disadvantages of aortic root surgery?

Lasts longer Requires warfarin May require re-operation

What are the features of cascade screening?

3 generation family history | Arrange ECG for first-degree relatives