34. Genetics and Cardiovascular Disease Flashcards
What are the causes for congenital heart disease? (6)
- chromosomal
- microdeletions
- single gene
- teratogens
- multifactorial
- other
What are examples of chromosomal conditions? (2)
- trisomies
2. monosomies
What are examples of microdeletions? (2)
- 22q11 deletion
2. William’s syndrome
What are examples of single gene congetial heart conditions? (6)
- Noonan/CFC
- Marfan’s
- SVAS
- Holt-Oram
- Fanconi
- CHARGE
What are examples of teratogens that cause heart conditions?
- rubella
- alcohol
- anti-epileptic drugs
- maternal DM
What is an example of “other” causes that cause heart conditions?
VACTERL
What is an example of multifactorial cause that lead to heart conditions?
Isolated congenital diaphragmatic hernia (CHD)
What kind of gene mutation is Down’s Syndrome?
Trisomy 21
95% maternal non-disjunction, 2% translocation and 2% mosaic
What do 15% Down’s Syndrome patients have?
atri-ventricular septal defects
Except from AV septal defects, what other condition do Down’s Syndrome patients often have?
Duodenal atresia
What is seen on an ultrasound in Down’s Syndrome babies that isn’t seen in healthy babies?
Nuchal translucency is bigger than in healthy babies ( collection of fluid under baby’s skin at the back of the neck)
What percent of fetuses with congenital heart disease have abnormal chromosomes?
19%; chromosome abnormality more common in foetuses in congenital heart disease
What is seen on an ultrasound that suggests a chromosomal abnormality?
cystic hygroma: lymphatic lesion
What percent of newborns with congenital heart disease have abnormal chromosomes?
13%
What kind of gene mutation is Turner’s Syndrome?
- 45, X
- 30% mosaic
- 5% 45 X/46XY
What is meant by mosaic?
Presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilised egg
What are the features of Turner’s Syndrome? (5)
- coarctation of the aorta
- short stature
- gonadal(ovarian) dysgenesis
- puffy hands
- infertility
What congenital condition causes neck webbing?
Noonan syndrome
What is neck webbing?
- excess nuchal folds
- seen in many congenital conditions
What are common features of Noonan Syndrome? (7)
- pulmonary stenosis
- short stature
- neck webbing
- cryptorchidism (absence of 1 or both testes from scrotum)
- characteristic face
- PTPN11 gene (chromosome 12) mutation
- autosomal dominant
What congenital conditions (syndromes) are associated with neck webbing? (5)
- Turner’s syndrome
- Noonan Syndrome
- CFC syndrome
- Leopard Syndrome
- Costello syndrome
What are features of CNC (cardiofaciocutaneous) syndrome? (3)
- Noonan-like
- ectodermal problems
- developmental delay
What are features of Leopard syndrome? (3)
- Noonan-like
- multiple lentigenes
- deafness
What are features of Costello syndrome? (5)
- Noonan-like
- thickened skin folds
- susceptible to warts
- cardiomyopathy
- later cancer risk
What do Noonan, CFC, Leopard, Costello and Turner’s syndrome all have in common? (2)
- All have changes to their genes in the same pathway (which can lead to neck webbing)
- All can be tested at the same time
Can Noonan, CFC, Costello, Turner’s and Leopard syndromes affect both genders?
All of them can EXCEPT Turner’s (which is only females)
What pathway do Noonan, Leopard, CFC, Turner’s and Costello syndromes all have in common?
MAPK (Mitogen activated protein kinase) pathway
What are the features of 22q11 deletion syndrome? (CATCH 22)
C=cardiac malformation A= abnormal faces T= thymic hypoplasia (underdeveloped thymus) C= cleft palate H= hypoparathyroidism 22=22q11 deletion
What 2 systems are generally affected by the 22q11 deletion syndrome?
- renal
2. psychiatric
22q11 deletion syndrome is a mixture of which two other syndromes?
- DiGeorge syndrome
2. Shprintzen Syndrome
What are the features of DiGeorge Syndrome? (4)
- thymic hypoplasia
- hypoparathyroidism
- outflow tract cardiac malformation
- usually sporadic (irregular)
What are the features of Shprintzen Syndrome? (4)
- cleft palate/ palatal insufficiency
- outflow tract cardiac malformation
- characteristic face
- autosomal dominant
What is common in 22q11 deletion syndrome?
- speech delay/ palatal dysfunction common
- variable disorder (can appear differently from patient to patient)
- low frequency (~1-2%) in unselected congenital heart disease
When to test for 22q11 deletion syndrome?
If patient has 2 or more features present (continue to look for additional clinical features)
Is 22q11 deletion syndrome familial?
Not necessarily, only ~25% is familial
What psychiatric effect does 22q11 deletion syndrome have?
22% of adult patients with 22q11 deletion have schizophrenia, 13% are bipolar and 2.5% have depression
What facial features are common in 22q11 deletion syndrome?
- small mouth
- floppy ears
- assymetric “crying” face
- long fingers and face (which become longer with age)
- bulbous nasal tips
- long nose
Why is 22q11 deletion a genomic condition?
- on the region of 22, part of the gene sequence is skipped (deletion) and keeps recurring along the DNA strand
What are features of William’s Syndrome?
- aortic stenosis (supravalvar)
- hypercalcaemia
- 5th finger clinodactyly
- characteristic face
- cocktail party manner
What genetic mutations occur in William’s syndrome?
- deletion of elastin on chromosome 7
- deletion of contiguous (next to each other) genes (LIM kinase)
How many units of alcohol per week can cause foetal alcohol syndrome?
3-5 units per week
What does foetal alcohol syndrome cause?
- intra-uterine growth restriction, growth retardation (IUGR)< 10th centile
- head<10th centile
- face
- ADHD
What are the most common teratogens?
- foetal alcohol syndrome
- antiepileptic drugs
- rubella
- maternal diabetes (mellitus in the mother)
Define teratogen.
Agent that causes malformation of the embryo
What pathway is affected by teratogens such as alcohol or antiepileptic drugs?
methylation system/ pathway (which produces an irregular gene pattern)
What anti-epileptic drugs can cause foetal anticonvulsant syndromes? (3)
- valproate
- phenytoin
- carbamazepine
What are the features of foetal anticonvulsant syndromes? (3)
- characteristic faces
- malformation patterns
- developmental delay
What are the most common congenital heart disease that child is more likely to get if mother has it? (7)
- aortic stenosis
- patent ductus arteriosus
- cardiac anomaly
- atrial septal defect
- ventricular septal defect
- pulmonary stenosis
- tetralogy of Fallot
What is ventricular septal defect associated with?
folate deficiency (low folic acid intake)
What are common genetic cardiac connective tissue disease? (4)
- Marfan’s
- Loeys- Dietz
- Ehlers Danlos
- FTAA (familial thoracic aortic aneurysm)
What are common genetic cardiac familial arrhythmias? (4)
- long QT
- Brugada syndrome (dangerous heart rhythms)
- CPVT
- ARVC
What are common genetic cardiac familial cardiomyopathies? (2)
- hypertrophic cardiomyopathy
2. dilated cardiomyopathy
What type of gene mutation is Marfan’s? (2)
- Fibrillin 1 gene on chromosome 15q21 affected
- TGFBR2 and 1 gene on chromosome 3p22 (9q33) affected
- autosomal dominant
What systems and tissue type does Marfan’s affect?
Multisystem (many systems); affects connective tissue
What effect does Marfan’s have on the cardiovascular system? (2)
- aortic dilatation
2. aortic dissection
What effect does Marfan’s hae on the eyes? (1)
- ectopia lentis (malposition of the eye’s lens, lens flip out of place)
What effect does Marfan’s have on the other body systems? (6)
- skeletal
- skin
- respiratory
- dural ectasia
- mitral valve prolapse
- myopia (short-sighted)
What mutation is most commonly associated with Marfan’s?
Fibrillin 1 mutation
What family history can give an indication of Marfan’s?
unequivocally affected relative (e.g. father)
According to Ghent 2010 guidelines, what 5 things must be true to diagnose a patient with Marfan’s? (5)
- cardiovascular (effect)
- eyes (effect)
- family history
- Fibrillin 1 mutation
- Systemic score >=7
What skeletal features in the Systemic Score consideration are present in Marfan’s? (6)
- ULSR and SHR (tall, thin and arm span>height)
- Scoliosis/kyphosis
- pectus deformity
- thumb and wrist
- foot/ankle
- reduced elbow expansion <170 degrees
What other features in the Systemic Score consideration are present in Marfan’s? (6)
- Myopia> 3 dioptres (short sighted)
- MVP
- pneumothoraz
- dura
- striae
- face
- protrusio acetabuli (hip)
What investigations should be done for suspected Marfan’s?
- echocardiography
- MRI of lumbar spine
- Pelvic X ray
- chest x ray
Why is echo used for Marfan’s?
- mandatory
- assessing aortic root diameter at sinus of Valsalva
- reason for murmur can be clarified
Why is MRI of lumbar spine used for Marfan’s?
- may show dural ectasia (from Ghent’s diagnosis criteria)
Why is pelvic x ray used for Marfan’s?
- to check for protrusio acetabuli
Why is chest x ray used for Marfan’s?
- apical blebs might be seen
What are the most common Marfan’s features appearing from childhood into adulthood but NOT all at once? (9)
- tall stature
- pes plenus (arches of feet collapse)
- pectus deformity
- scoliosis
- face/palate
- myopia
- ectopia lentis
- aortic
- striae (stretch marks)
What signalling pathway is treated in Marfan’s syndrome?
TGFBeta pathway (excess TGFBeta present in Marfan’s)
What happens to levels of TGFBeta and Fibrillin in Marfan’s?
TGDBeta= increases
Fibrillin 1 = decreases (deficiency)
What are Marfan like syndromes? (4)
- Loeys- Dietz Syndrome
- Marfan Syndrome type 2 (non-ocular)
- Familial Thoracic Aortic Aneurysm
- MASS phenotype
What are features of Loeys-Dietz syndrome which is Marfan-like? (5)
- arterial dissection
- turtuosity (misshapen aorta)
- bifid uvula/cleft palate
- hypertelorism (increased distance between eyes)
- skin and skeletal findings
What are features of MASS pheonotype which is Marfan- like? (5)
- myopia (short sighted)
- mitral valve prolapse
- mild aortic dilatation
- striae
- minor skeletal involvement
What are the management options for Marfan’s? (5)
- echo
- beta blockers
- angiotensin II receptor blocker (ARBs)
- prophylactic aortic surgery if sinus of valsalva exceeds 5.5cm or 5% growth per year (2mm in adults)
- monitor aortic root frequently in pregnancy if diameter exceeds 4cm
Marfan’s patient who are on aortic root surgery should be put on what medication?
Warfarin (anticoagulants)
What is sudden unexpected death syndrome caused by?
- undiagnosed arrhythmia syndrome
- 1/3 show no post mortem cause
- most patients had familial predisposition to arrhythmias
Which genetic cardiac disorders have ion channelopathies as their site of lesion? (5)
- long QT syndrome (LQT)
- Brugada syndrome
- CPVT
- progressive cardiac conduction defect (PCCD)
- short QT syndrome (SQT)
Which genetic cardiac disorder has sarcomere as its site of lesion?
Hypertrophic cardiomyopathy
Which genetic cardiac disorder has cell junction as its site of lesion?
Arrhythmic right ventricular cardiomyopathy (ARVC)
Which genetic cardiac disorder has cytoskeleton as its site of lesion?
dilated cardiomyopathy
What happens during long QT syndrome?
- Romano-Ward syndrome
- myocytes take longer to recover which predispose patient to fainting and arrhythmias
- repolarisation anomaly
What are the typical features of long QT syndrome?
- patient has seizure-like symptoms
- syncope common
- sudden death can arise
- patient should always have ECG to confirm patient doesn’t have arrthymias
- emotion, exercise and drugs can make it worse
What is the T-wave pattern on ECG and mutation associated with arrhythmia caused by exercise e.g. swimming?
- normal/broad T wave pattern on ECG
- KCNQ1 utation
What is the T-wave pattern on ECG and mutation associated with arrhythmia caused by noise/arousal e.g. ringing telephone?
- notched T wave pattern on ECG
- KCNH2 mutation
What is the T-wave pattern on ECG and mutation associated with arrhythmia caused by sleep/bradycardia?
- biphasic T wave pattern on ECG
- SCN5A
What genes are screened for in long QT syndrome? (5)
- KCNQ1
- KCNH2
- SCN5A
- KCNE1
- KCNE2
What are common indicators of a long QT syndrome? (7)
- abnormal ECG
- arrhythmia
- family history
- sudden death
- seizures
- syncope
- unknown/other
Why is genotyping useful?
- improves prognosis (outcome)
- lifestyle changes can be made if needed (antihistamines , extreme sports etc)
What is the treatment for long QT syndrome types 1,2,3 and 6? (2)
- beta blockers
- nicorandil (used for angina usually)
What is the treatment for long QT syndrome type 3? (3)
- mexilitene
- lidocaine
- ICD; implantable cardioverter defibrillator
With which genetic mutation is the Brugada syndrome associated with?
SCN5A mutation
What is the prevalence and presentation of hypertrophic cardiomyopathy?
- prevalence is 1/500
- presentation is variable, sudden death more common if diagnosed <14 years or symptomatic
What are modifiers for hypertrophic cardiomyopathy? (2)
- lifestyle (e.g. sports)
- other genes (e.g. ACE polymorphism)
What are the most common MONOALLELIC genotypes for hypertrophic cardiomyopathy? (4)
- MYH7 (beta cardiac myosin)
- MYBPC3 (myosin binding protein-MOST COMMON)
- TNNT2 (cardiac troponin)
- TNNI3 (cardiac troponin)
What are the most coomon DIALLELIC genotypes for hypertrophic cardiomyopathy? (2)
- MYH7
- MYBPC3/TNNT2
What is ARVC: arrhythmogenic right ventricular cardiomyopathy?
- effort induced polymoprhic tachycardia
- right ventricular cardiomyopathy (dilated)
- disordered cell junctions (cells lose communication)
- T wave inversion V2-3 on resting ECG
What type of gene mutation is ARVC: arrhythmogenic right ventricular cardiomyopathy?
Autosomal dominant >12 genes (cell junction genes)
What are the most common cell junction genes which are altered in ARVC: arrhythmogenic right ventricular cardiomyopathy? (8)
- PKP2
- DSG2
- DSP
- Desmocillin 2
- Plakoglobin
- TMEM43
- TGFB3
- RYR2
What must there be evidence of to suspect dilated cardiomyopathy? (3)
- syncope or pre-syncope
- tachy or brady arrhythmia
- evidence of any arrhythmia on ECG
What is the differential diagnosis in dilated cardiomyopathy? (6)
- ischaemic heart disease
- hypertension
- skeletal muscle diseas e
- alcohol abuse
- exposure to cardiotoxic drugs
- haemochromatosis
- mitochondrial disorder
What investigation can exclude ischaemic heart disease from dilated cardiomyopathy?
angiography
What investigation can exclude skeletal muscle disease from dilated cardiomyopathy? (2)
- neurology/genetics evaluation
- CPK (creatine phosphokinase)
What investigation can exclude alcohol abuse from dilated cardiomyopathy? (2)
- patient’s history
- biochemical evidence
What investigation can exclude exposure to cardiotoxic drugs from dilated cardiomyopathy?
-patient history
What investigation can exclude haemochromatosis from dilated cardiomyopathy? (2)
- ferritin test (iron storage protein)
- genotyping
When should you consider mitochondrial disease in a patient suspected of dilated cardiomyopathy? (5)
If patient has:
- diabetes
- deadness
- renitis pigmentosa
- skeletal muscle disease
- growth retardation or cognitive disorder (mental health disorder and development)
What feature of family history should indicate likeliness of dilated cardiomyopathy in a patient? (2)
- family history of cardiomyopathy
- sudden cardiac death of a family member
What genetic testing may be required in dilated cardiomyopathy patient? (4)
- LMNA gene
- SCN5A
- dystrophin
- sarcomere genes
What are the steps for cascade screening for patient’s with suspected cardiac disease?
- do a 3 generation family history
- arrange ECGs for first degree relatives
- compare ECG results
What type of screening is undertaken for patient’s relatives to test for cardiac disease?
cascade screening
Why is genetic screening important?
- prevention of avoidable morbidity and mortality
What steps should be taken when genetically screening a patient for cardiac disease? (3)
- Identify cardiac phenotype and genetic testing
- look at family history
- assess relatives
