Genetics + CV Disease Flashcards
What are the causes of congenital heart disease?
- Chromosomal
- Microdeletions
- Single gene
- Teratogens
- Multifactorial
- Other
Give examples of chromosomal causes of CHD.
- Trisomies
- Monosomies
Give examples of microdeletion causes of CHD.
- 22q deletion
- Williams
Give examples of single gene causes of CHD.
- Noonan/CFC
- Marfans
- SVAS
- Holt-Oram
- Fanconi
- CHARGE
Give examples of teratogen causes of CHD.
- Rubella
- Alcohol
- Anti-epileptic drugs
- Maternal Diabetes mellitus
Give examples of other causes of CHD.
VACTERL
What are the causes of trisomy 21?
- 95% maternal non-disjunction
- 3% translocation
- 2% mosaic
What is other medical conditions are associated with Downs Syndrome?
- Atrio-ventricular septal defects
- Duodenal atresia
How is Down’s Syndrome often identified in utero?
- Measurement of nuchal translucency
- Increased nuchal translucency
Why are chromosome abnormalities more common in foetuses with CHD than in new-borns?
Many foetuses result in miscarriage and therefore never make it to term
What are foetuses with CHD and abnormal chromosomes associated with?
Cystic hygroma on scans
What is the genetic make up of Turner Syndrome?
45,X
What are the clinical signs of Turner Syndrome?
- Coarctation of aorta
- Short stature
- Gonadal dysgenesis
- Puffy hands
What is neck webbing?
- Excess nuchal folds
- An indicator of prenatal cardiac difficulties
What syndromes are associated with neck webbing?
- Turner
- Noonan
- CFC
- Leopard
- Costello
What are the clinical signs of Noonan syndrome?
- Pulmonary stenosis
- Short stature
- Neck webbing
- Cryptorchidism
- Characteristic face
What is the cause of Noonan Syndrome?
PTPN11 mutation on gene on chromosome 12
What type of inheritance is there with Noonan syndrome?
-Autosomal dominant
What are the clinical signs of Cardio-Facio-Cutaneous syndrome?
- Noonan like
- Ectodermal problems
- Developmental delay
What are the clinical signs of Leopard syndrome?
- Noonan like
- Multiple lentigenes
- Deafness
What are the clinical signs of Costello syndrome?
- Noonan like
- Thickened skin folds
- Susceptible to warts
- Cardiomyopathy
- Later cancer risk
What pathways are Noonan, Leopard, Costello, and CFC syndromes all linked to?
MAPK pathway (mitogen activated protein kinase pathway)
What are the clinical signs of 22q11 deletion syndrome?
- Cardiac malformation
- Abnormal facies
- Thymic hypoplasia
- Cleft palate
- Hypoparathyroidism
What are the facial characteristics associated with 22q11 deletion syndrome?
- Narrow eyes
- Small mouth
- Very floppy overfolded ears
- Bulbus nose
What 2 syndromes does 22q11 encompass?
- DiGeorge
- Shprintzen
What are the characteristics of DiGeorge syndrome?
- Thymic hypoplasia
- Hypoparathyroidism
- Outflow tract cardiac malformation
- Usually sporadic
What are the characteristics of Shprintzen syndrome?
- Cleft palate/palatal insufficiency
- Outflow tract cardiac malformation
- Characteristic face
- Autosomal dominant
What other characteristics are associated with 22q11 deletion syndrome other than CATCH?
- Speech delay
- Palatal dysfunction
- Renal problems
- Psychiatric conditions
When should an individual be tested for 22q11 deletion syndrome?
If there are 2 or more features present
What 3 psychiatric conditions are associated with 22q11 deletion syndrome?
- Schizophrenia
- Depression
- Bipolar affective
Is 22q deletion a genomic disease?
- There are low copy repeats
- Predisposition to deletion and translocation
What are the clinical signs of Williams syndrome?
- Aortic stenosis
- Hypercalcemia
- 5th finger clindactyly
- Characteristic face
- Cocktail party manner
What is the cause of Williams syndrome?
- Deletion of elastin on chromosome 7
- Deletion of contiguous genes
- LIM kinase
What are the clinical signs of foetal alcohol syndrome?
-Hearing loss
-Visuomotor difficulties
-Fine motor difficulties
Long philtrum
-Thin upper lip
-Increased eye spacing
-ADHD
-Small head
-Low IUGR
What anticonvulsants are known teratogens?
- Valproate
- Phenytoin
- Carbamazepine
What are the clinical signs of foetal anticonvulsant syndromes?
- Characteristic face
- Malformation patterns
- Developmental delay
- Common and specific features
What model explains the increased recurrence risk of first degree relatives despite the same threshold as the normal population?
Multifactorial inheritance threshold model
Which parent has more influence on their child having CHD?
Mother
What is VSD associated with?
Folate deficiency
What are 3 types of genetic cardiac diseases?
- Cardiovascular connective tissue disease
- Familial arrhythmias
- Familial cardiomyopathy
Give examples of cardiovascular connective tissue diseases.
- Marfan
- Loeys-Dietz
- Ehlers Danlos
- FTAA
Give examples of familial arrhythmias.
- Long QT
- Brugada
- CPVT
- ARVC
Give examples of familial cardiomyopathies.
- HCM
- DCM
What type of inheritance is Marfan syndrome?
Autosomal dominant
What gene is involved in Marfans?
- Fibrillin 1 gene on chromosome 15q21
- TGFBR2 on chromosome 3p22
What is true of the Ghent 2010 criteria for a diagnosis of Marfans?
2 system findings that are positive
What are the system components of the Ghent criteria?
- CV system
- Eyes
- Systemic score >/= 7
- Family history
- Fibrillin 1 mutations
What are the skeletal features of the systemic score on the Ghent criteria?
- ULSR and SHR
- Scoliosis/kyphosis
- Pectus deformity
- Thumb and wrist (thumb over hand/ pinky to thumb round wrist)
- Foot/ankle (inwards bend)
- Reduced elbow extension <170 degrees
Apart from skeletal what are the there features of the systemic score on the Ghent criteria?
- Myopia>3 dioptres
- Mitral valve prolapse
- Pneumothorax
- Dural ectasia
- Striae
- Face
- Protusio acetabuli
Most features of Marfans are assessed clinically. When should additional tests be done?
- ECHO mandatory
- Undertake MRI and/or pelvic X-ray where diagnosis would change if positive
What eye condition is associated with Marfans?
Ectopia lentis
What CV conditions are associated with Marfans?
Aortic dilation/dissection
What is usually the first sign noticed with Marfans?
Tall stature
When should you do a genetic test in suspected index case of Marfans?
When a positive result would change the diagnosis
What must be true of the Ghent criteria to make a positive diagnosis of Marfans?
- 2 major features
- 1 major and 2 minor features
- Ghent score of 7 or over
Give examples of Marfan like syndromes.
- Loeys-Dietz syndrome
- Marfan syndrome type 2
- Familial thoracic aortic aneurysms
- MASS phenotype
What is Loeys-Dietz syndrome associated with?
- Arterial dissection
- Tortuosity
- Bifid uvula/cleft palate
- Hypertelorism
- Skin and skeletal findings
What is MASS phenotype associated with?
- Myopia
- Mitral valve prolapse
- Mild aortic dilatation
- Striae
- Minor skeletal involvement
What is the optimal management for Marfans?
At least annual clinical review:
- ECHO
- B blockers
- Angiotensin II receptor blocker
- Prophylactic aortic surgery if Sinus of Valsalva exceeds 5.5cm or 5% growth per year
- Monitor aortic root frequently in pregnancy if diameter exceeds 4cm
Why should B blocker therapy be considered in all Marfan patients?
To slow the rate of dilatation
What are the pros and cons of mechanical valves?
Pros
-Lasts longer
Cons
-Needs warfarin
What are the pros and cons of valve sparing procedures?
Pros
-No warfarin
Cons
-May need reoperation
What is another name of long QT syndrome?
Romano-Ward syndrome
What is the pathophysiology of long QT syndrome?
Myocytes take longer to recover than they should
What is seen on ECG of long QT syndrome?
- Prolonged QT interval
- Repolarisation anomalies (T/U waves)
- Paroxysmal polymorphic VT
What are the manifestations of long QT syndrome?
- Syncope
- Seizure
- Sudden death
What can trigger long QT syndrome?
- Emotion
- Exercise
- Drugs
How does Jervell Lange-Neilsen differ from long QT syndrome?
Includes congenital sensorineural deafness
What is the genotype prediction of normal/broad T wave precipitated by exercise, in particular swimming?
KCNQ1
What is the genotype prediction for notched T wave precipitated by noise/arousal such as a telephone or alarm clock?
KCNH2
What is the genotype prediction for biphasic T waves precipitated by sleep/ bradycardia?
SCN5A
What is included in genetic testing for LQT in Scotland?
Full mutation screening of:
- KCNQ1
- KCNH2
- SCN5A
- KCNE1
- KCNE2
What is the treatment for LQT?
- 1/2, 5/6 B blockers, nicorandil
- 3 mexilitene/lidocaine/ICD
What is Brugada syndrome associated with?
- Right bundle branch block
- QT normal
- ST elevation in leads 1-3
- Episode VT/VF
- Rest and sleep
- Also SCN5A associated
What is the prevalence of hypertrophic cardiomyopathy?
1/500
What is associated with arrythmogenic right ventricular cardiomyopathy?
- Effort induced polymorphic tachycardia (LBBB pattern)
- Right ventricular cardiomyopathy
- T wave inversion V2-3 on resting ECG
- Disordered cell junctions
What type of inheritance is associated with ARVC?
Autosomal dominant
What genes are involved in ARVC?
- Plakophilin 2
- Desmoglein 2
- Desmoplakin
- Desmocollin 2
- Plakoglobin
- TMEM43
- TGRB3
- RYR2
What history is associated with dilated cardiomyopathy?
Syncope or pre-syncope compatible with tachy or brady arrhythmia, or evidence of arrhythmia on ECG investigation
What conditions should be excluded when diagnosing dilated cardiomyopathy?
-Ischaemic heart disease
-Hypertension
-Skeletal muscle disease
-Alcohol abuse
-Exposure to cardio toxic drugs
Haemochromatosis
When should mitochondrial disorder be considered when diagnosing dilated cardiomyopathy?
If there is:
- Diabetes
- Deafness
- Retinitis pigmentosa
- Skeletal muscle disease
- Growth retardation
- Cognitive disorder
What family history should be evident with dilated cardiomyopathy?
FH of cardiomyopathy or sudden cardiac death compatible with cardiomyopathy
What may genetic testing of dilated cardiomyopathy include?
- LMNA
- SCN5A
- Dystrophin
- Sarcomere genes
What is cascade screening?
- Do a 3 generation family history
- Arrange ECGs for 1st degree relatives
What does cardiac genetics involve?
- Diagnosis in proband (cardiac phenotype and genetic testing)
- Family history
- Assess relatives
- Cascade screening of relatives
- Prevention of avoidable morbidity and mortality
