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R-Cradio-illness > Genetics of Cardiovascular Disease > Flashcards

Genetics of Cardiovascular Disease Flashcards

1
Q

What are the causes of congenital heart defects?

A

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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2
Q

Down syndrome is caused by trisomy of what chromosome?

A

Trisomy 21

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3
Q

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

A

95% maternal non-dysjunction

Associated with maternal age

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4
Q

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

A

3% translocation

2% mosaic

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5
Q

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

A

15%

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6
Q

What congenital abnormalities might a baby with Down syndrome have?

A

Atrioventricular septal defect
Duodenal atresia
Nuchal translucency

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7
Q

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

A

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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8
Q

What is Turner syndrome?

A

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

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9
Q

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

A

30%

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10
Q

Turner syndrome is present in how many live births?

A

1/3000

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11
Q

What cardiovascular abnormality is seen in Turner syndrome?

A

Coarctation of the aorta

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12
Q

What are the features of Turner syndrome?

A

Short stature
Gonadal dysgenesis
Puffy hands
Neck webbing

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13
Q

What are the single gene disorder causes of neck webbing?

A 
Turner syndrome
Noonan syndrome
CFC syndrome
Leopard syndrome
Costello syndrome
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14
Q

What is the gene affected in Noonan syndrome?

A

PTPN11 gene

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15
Q

What are the features of Noonan syndrome?

A

Short stature
Neck webbing
Cryptorchidism
Characteristic face

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16
Q

What cardiovascular abnormality is associated with Noonan syndrome?

A

Pulmonary stenosis

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17
Q

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

A

Noonan-like appearance
Ectodermal problems
Developmental delay

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18
Q

What are the features of Leopard syndrome?

A

Noonan-like appearance
Multiple lentigines
Deafness

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19
Q

What are the features of Costello syndrome?

A 
Noonan-like appearance 
Thickened skin folds
Susceptibility to warts
Cardiomyopathy 
Cancer risk in later life
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20
Q

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

A

CATCH 22

C - cardiac malformation
A - abnormal facies
T - thymic hypoplasia
C - cleft palate
H - hypoparathyroidism
22 - 22q11 deletion
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21
Q

What are the other features of 22q11 deletion syndrome?

A

Renal and psychiatric problems
Speech delay
Palatal dysfunction
Very variable disorder

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22
Q

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

A

If 2 or more clinical features are present

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23
Q

What percentage of 22q11 deletion syndrome is familial?

A

25%

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24
Q

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

A

Around 1-2%

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25
Q

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

A

Linked with schizophrenia, depression and bipolar affective disorder

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26
Q

What syndromes are encompassed by 22q11 syndrome?

A

DiGeorge and Shprintzen (velocardiofacial)

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27
Q

What are the features of DiGeorge syndrome?

A

Thymic hypoplasia
Hypoparathyroidism
Outflow tract cardiac malformation
Usually sporadic

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28
Q

What are the features of Shprintzen syndrome?

A

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

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29
Q

What cardiovascular abnormality is associated with Williams syndrome?

A

Aortic stenosis (supravalvular)

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30
Q

What are the features of Williams syndrome?

A

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

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31
Q

What genetic abnormalities are seen in Williams syndrome?

A

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

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32
Q

What are the common teratogens?

A 
Alcohol - foetal alcohol syndrome 
Illicit drugs
Anti-epileptic drugs 
Rubella 
Maternal diabetes mellitus if poorly controlled
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33
Q

What are the features of foetal alcohol syndrome?

A 
Intrauterine growth restriction < 10th centile
Head < 10th centile
Characteristic face
ADHD
3-5 units per week
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34
Q

What are the features of foetal anticonvulsant syndrome?

A

Characteristic face
Malformation patterns
Developmental delays
Common and specific features

35
Q

What drugs might cause foetal anticonvulsant syndrome?

A

Valproate
Phenytoin
Carbamazepine

36
Q

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

A

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

37
Q

What are the genetic familial arrhythmias caused by genetic abnormalities?

A

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

38
Q

What are the familial cardiomyopathies caused by genetic abnormalities?

A

Hypertrophic cardiomyopathy

Dilated cardiomyopathy

39
Q

What are the genetic features of Marfan syndrome?

A 
Autosomal dominant 
Fibrillin 1 gene
Chromosome 15q21
TGF beta R2
Chromosome 3p22
40
Q

What are the cardiovascular features of Marfan syndrome?

A

Aortic dilatation/disection

41
Q

What condition of the eyes is caused by Marfan syndrome?

A

Ectopia lentis

42
Q

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

A 
Skeletal
Skin
Respiratory 
Dural ectasia
Mitral valve prolapse
Myopia
43
Q

What are the skeletal features of Marfan syndrome?

A 
USLR and SHR
Scoliosis/kyphosis 
Pectus deformity
Thumb and wrist
Foot/ankle
Reduced elbow extension
44
Q

What are the non-skeletal features of Marfan syndrome?

A 
Myopia
MVP
Pneumothorax
Dura
Striae
Face
Protrusio acetabuli
45
Q

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

A

Unequivocally affected relative

46
Q

Mutation of what gene is known to cause Marfan syndrome?

A

Fibrillin 1

47
Q

What is needed for diagnosis using the Ghent 2010 criteria?

A

2 system findings must be positive

48
Q

What investigations are needed in Marfan syndrome?

A

Echocardiography mandatory in all cases

Undertake MRI and/or pelvic x-ray where diagnosis would change if positive

49
Q

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

A

92%

50
Q

What percentage of Marfan syndrome patients are affected by protrusion?

A

47%

51
Q

What are the features of Loeys-Dietz syndrome?

A 
Arterial dissection
Tortuosity
Bifid uvula/cleft palate
Hypertelorism
Skin and skeletal findings
52
Q

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

A 
11q
5q
3p22
16p13
10q22-24
53
Q

In MASS phenotype, what does MASS stand for?

A

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

54
Q

What are the features of MASS phenotype?

A 
Myopia
Mitral valve prolapse
Mild aortic dilatation
Striae
Minor skeletal involvement
55
Q

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

A

Arrhythmic

56
Q

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

A

40-53%

57
Q

What are the features of long QT syndrome?

A

Syncope
Seizure
Death

58
Q

What is long QT syndrome brought on by?

A

Emotion
Exercise
Drugs

59
Q

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

A

Prolonged QT interval
Repolarisation anomalies
Paroxysmal polymorphic VT

60
Q

What are the features of Jervell Lange-Neilsen syndrome?

A

Same features as long QT plus congenital sensorineural deafness

61
Q

What is the prevalence of hypertrophic cardiomyopathy?

A

1/500

62
Q

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

A

If diagnosed < 14 years old, or symptomatic

63
Q

What is the mortality of hypertrophic cardiomyopathy?

A
  1. 9% per year diagnosed clinically in childhood
  2. 5% per year diagnosed clinically in adult life
  3. 5% per year diagnosed through screening
64
Q

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

A

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

65
Q

What are the cell junction genes affected by ARVC?

A 
Plakophilin 2
Desmoglein 2
Desmoplakin
Desmocollin
Plakoglobin
TMEM43
TGFB3
RYR2
66
Q

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

A

20%

67
Q

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

A

12-14%

68
Q

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

A

6-15%

69
Q

What are the features of dilated cardiomyopathy?

A

Echocardiographic features of dilated cardiomyopathy

History of syncope or pre-syncope compatible with brady/tachy-arrhythmia, or evidence of arrhythmia on ECG

70
Q

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

A 
If there is:
Diabetes
Deafness
Retinitis pigmentosa
Skeletal muscle disease
Growth retardation
Cognitive disorder
71
Q

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

A

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

72
Q

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

A

LMNA
SCN5A
Dystrophin
Sarcomere genes

73
Q

What conditions should be excluded in dilated cardiomyopathy?

A 
Ischaemic heart disease
Hypertension
Skeletal muscle disease
Alcohol abuse
Exposure to cardio toxic drugs
Haemochromatosis
74
Q

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

A

70-90%

75
Q

What Marfan patients have a better cardiovascular prognosis?

A

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

76
Q

When should genetic testing be done for Marfan patients?

A

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

77
Q

What results in the proteolytic release of TGF-beta?

A

Incorporation of fibrillin into microfibrils

78
Q

What does TGF beta signalling affect?

A

Cell proliferation, differentiation and apoptosis

79
Q

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

A 
KCNQ1
KCNH2
SCN5A
KCNE1
KCNE2
80
Q

What are the advantages of genotyping?

A

Allow determination of prognosis
Lifestyle alterations
Treatment

81
Q

What is the optimal management of Marfan syndrome?

A

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)

82
Q

What are the advantages and disadvantages of aortic root surgery?

A

Lasts longer
Requires warfarin
May require re-operation

83
Q

What are the features of cascade screening?

A

3 generation family history

Arrange ECG for first-degree relatives

R-Cradio-illness (27 decks)

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