Genetics and CVS disease Flashcards by Michael Alcorn

What is meant by Copy number variation?

Cause of congenital defects (incl. Congenital heart disease)

Can be whole chromosome - monosomy, trisomy

Can be part of a chromosome - 22q11 deletion, Williams

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What is meant by single nucleotide variation?

Mutation in which single nucleotide is fucked up

Mendelian disorders:

Noonan/CFC
Marfan
SVAS
Holt-Oram

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What causes Down’s syndrome?

Trisomy 21

95% maternal non-disjunction (mat age)
3% translocation
2% mosaic

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How is Down’s syndrome relevant to the Cardiovascular system?

15% born with Atrial septal defect

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How does Down’s syndrome affect the digestive system’s development?

8% born with Duodenum atresia

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How would an ultrasound scan indicate that a foetus may have Down’s syndrome?

Nuchal translucency

This is a translucent area on the back of the neck at 12 weeks - thickness of area measured

Nuchal prenatal screening scan is done to detect abnormalities of the CVS & can indicate risk of Down’s S etc

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What is the name given to blocked lymphatic fluid that is trapped, commonly in the head/neck area of a developing foetus?

Cystic hygroma

Associated with congenital HD

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What percentage of foetuses with congenital heart diseases have abnormal chromosomes?

19%

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What percentage of new borns with congenital heart diseases have chromosomal abnormalities?

13%

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What chromosomal abnormality causes Turner’s syndrome?

45, X

30% mosaic

5% 45,X/46XY

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What are the signs/effects of Turner syndrome?

Neck webbing
Short stature
Puffy hands

Coarctation of aorta
Gonadal dysgenesis

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Is neck webbing only associated with Turner syndrome?

No, the syndromes with webbed necks are:

Turner
Noonan
CFC 
Leopard 
Costello

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How would you identify Noonan syndrome?

Neck webbing
Short stature
Cryptorchidism (testis don’t drop from abdomen)
Characteristic face

Pulmonary stenosis

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How would you identify Cardio-Facio-Cutaneous syndrome? (CFC)

Ectodermal problems
Developmental delay

Noonan like:

Neck webbing
Short stature
Cryptorchidism
Characteristic face
Pulmonary stenosis

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How would you identify Leopard syndrome?

Noonan like

Also:

Multiple lentigenes (brown patches on skin)
Deafness

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How would you identify Costello syndrome?

Noonan like but with:

Thickened skin folds
Warts
Cardiomyopathy
Later cancer risk

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Leopard, Costello, CFC & Noonan syndromes are all associated with defects in enzymes in what cellular pathway?

MAPK pathway

Mitogen activated protein kinase

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How would you identify 22q11 deletion syndrome?

CATCH22

Cardiac malformation 
Abnormal facies (distinct facial look/expression) 
Thymic hypoplasia 
Cleft palate 
Hypoparathyroidism

22q11 deletion

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What functional abnormalities are experienced by people with 22q11 DS?

(assuming any defects at birth are fixed)

Renal

Psychiatric

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What 2 syndromes make up 22q11 DS?

DiGeorge syndrome

Shprintzen syndrome

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What factors of 22q11 DS does DIGeorge syndrome account for?

Thymic hypoplasia
Hypoparathyroidism
Outflow tract myocardial malformation

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What factors of 22q11 ds does Shprintzen syndrome account for?

Cleft palate / malformation of palate
Outflow tract myocardial malformation
Facies (face)
Autosomal dominance

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How would you identify William’s syndrome?

Aortic stenosis - supravalvular 
Hypercalcaemia 
5th finger clinodactyly - bent pinky 
Facies 
Cocktail party manner

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What causes Williams syndrome?

Deletion of several continuous genes on the long arm of chromosome 7 including elastin and LIM kinase

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What is the risk and effects of consuming alcohol when pregnant?

Foetal alcohol syndrome - 3-5 units per week ``` Effects: IUGR < 10th centile Head < 10th centile ADHD Face ``` (IUGR = intrauterine growth restriction)

One of the JAMTHREADS drugs for treatment is teratogenic Which one is it?

Epilepsy Antiepileptics are teratogenic

Contraction of what can cause german measles?

Rubella

What JAMTHREADS illness is teratogenic in itself?

Diabetes

Which parent is more generally likely to pass on a simple congenital heart disease?

Mother

VSD is associated with deficiency of what necessary vitamin thing?

Folate

What are the cardiovascular connective tissue diseases?

Marfan Loeys-Dietz Ehlers Danlos FTAA

What are the different Familial arrhrythmias?

Long QT Brugada CPVT ARVC

What are the different familial cardiomyopathy diseases?

Hypertrophic cardiomyopathy Dilated cardiomyopathy ARVC

Mutation of what gene causes Marfan's syndrome?

Fibrillin 1 gene | Chromosome 15q21

What system is used to diagnose Marfan's syndrome?

GHENT criteria 2010 Must have 2 positive findings

Describe the GHENT criteria

Aortic dilation/dissection Ectopia lentis Fibrillin 1 mutation 1 unequivocally affected relative Systemic score - must have 7 or more of: - Skeletal - Skin - Respiratory - Dural ectasia (dilation of dural sac around spinal cord) - Mitral valve prolapse - Myopia (short sightedness)

Why is ECHO useful for diagnosing Marfan's

ECHO is mandatory Measure diameter of aortic root at sinus of Valsalva, showing extent of dilation Identify mitral valve prolapse

Why could a blood test be useful for diagnosing Marfan's?

Genome sequencing (or other) can identify Fibrillin 1 gene mutations This is identifiable in 70-90% of people with Marfan's

Why is an X ray a useful imaging technique for diagnosing Marfan's syndrome?

Pelvic Xray will identify Protrusio acetabulae (skeletal feature) CXR (or CT) can identify Apical blebs (Respiratory feature)

Why are MRI's useful for diagnosing Marfan's?

Lumbar MRI will identify Dural ectasia Cardiac MRI will identify aortic dilation/dissection

Even if a father and son both have Marfan's syndrome, they might show different symptoms & signs Why is this?

Different symptoms present at different times

Summarise the treatment for Marfan's syndrome

Prophylactic: Antihypertensives - Beta blockers, ARBs, ANG2 type 2 receptor blockers, calcium channel blockers Aortic root surgery - if sinus of Valsalva > 5.5cm or 5% growth per year Advice to avoid contact sports and heavy exertion Annual review - ECHO

What findings on an ultrasound scan of a foetus would indicate an increased risk of congenital heart disease?

Nuchal translucency thickness Cystic hygroma

Mutations involving what gene & chromosome give rise to Noonan syndrome and Noonan-like syndromes?

PTPN11 On chromosome 12

What type of trait is Noonan syndrome?

Autosomal dominant | pretty much all of the syndromes in this lecture are autosomal dominant

What is CPVT?

Catecholaminergic polymorphic ventricular tachycardia It is one of the familial arrhythmias

What is ARVC?

Arrhythmogenic right ventricular cardiomyopathy One of the familial arrhythmias (although it has a cardiomyopathy aspect as well)

What would be a typical signs on presentation of someone that has Marfan's?

Tall with long arms Hypermobile/flexible Stretch marks on lower back Pectus carinatum History of myopia, lung problems Family history of Cardio disease and tallness and all that shite

What are the main features of Loeys-Dietz syndrome?

Marfan's like signs Arterial weakening / dissection Tortuosity Bifid uvula / cleft palate Hypertelorism - increased distance between the eyes skin and skeletal findings

What mutation causes loeys-dietz?

Chromosome 3p22 or 9q33

What chromosomal mutations are associated with Familial thoracic aortic aneurysms?

``` 11q 5q 3p22 16p13 10q22-24 ``` Bicuspid aortic valve FTAA

What features characterise the MASS phenotype?

``` myopia mitral valve prolapse mild aortic dilatation (<2sd) striae minor skeletal involvement May be fibrillinopathy ```

What arrhythmia is associated with ion chanellopathy and why is it relevant to Sudden Unexpected Death?

Autopsy of people with SUD showed that 35% had ion channelopathy The majority of these is Long QT syndrome

Some study that was done studied the relatives of people who had Sudden unexpected death What did this investigation show?

40-53% of SUD patient's 1st degree relatives had an identifiable inherited heart disease basically indicates that inherited heart diseases put patient at risk of Sudden unexpected death

What is Romano-ward syndrome?

Form of Long QT syndrome Key feature is that only the conduction properties of the heart are affected whereas other long QT syndromes have effects elsewhere in the body

What are the risks posed to someone with Romano-Ward syndrome?

Syncope Seizures Sudden Death

What features of an ECG would indicate Romano-Ward syndrome?

Long QT interval Repolarisation anomalies (T/U waves) Paroxysmal polymorphic VT (Torsades de Pointes)

What is Jervell Lange-Neilsen syndrome?

Almost identical to Romano-Ward syndrome Form of Long QT syndrome with risks of Syncope, seizures and sudden death + sensorineural deafness !

What are the main features of Brugada syndrome?

Sudden cardiac death or VT/VF and Type 1 Brugada ECG prolonged PR interval enlarged LV / poor LV function

What group of people is Brugada syndrome most common in?

Young men, especially of far eastern origin

What is the test done to diagnose Brugada syndrome?

Ajmaline challenge

What mutation most commonly causes Brugada syndrome?

SCN5A

What is the management route for Brugada syndrome?

``` Avoid Fever Avoid excess alcohol Avoid overeating (- Vagal effects) ``` ICD

What is AVC?

Atrioventricular canal defect ASD + VSD + Improperly formed Mitral and/or Tricuspid valves

How is Atrioventricular canal investigated?

ECHO / CMRI (RV dyskinesia) ECG - epsilon waves , T wave inversion SAECG - late potentials Family history / investigation of pathogenic gene variant

What histological abnormality is present in Atrioventricular canal patients?

Fatty infiltration of Right Ventricle

What is the prevalence of Hypertrophic cardiomyopathy?

1/500

What HCM patients are most at risk of sudden cardiac death?

SCD most common in those diagnoses <14 years old Or in those who are symptomatic

What are the modifiers for the prognosis of a patients with HCM?

Lifestyle - sport etc Other genes - eg ACE polymorphism

Which allelic form of HCM is most common?

Monoallelic Most common is Myosin binding protein gene mutation (MYBPC3)

What histological feature is present in H(O)CM?

Myofibrillar disarray

What are the steps in investigating / diagnosing Dilated cardiomyopathy?

ECHO Exclude other conditions Family history - look for history of SCD or cardiomyopathy evidence Genetic testing

What genetic testing for what genes may be done to investigate Dilated cardiomyopathy?

``` Titin LMNA SCN5A Dystrophin Sarcomere genes ```

What is the difference between whole genome sequencing and whole exome sequencing?

Exome sequencing only involves the parts of genes that code for proteins

Genetics and CVS disease Flashcards

(74 cards)