Genetics and Cardiovascular disease Flashcards
What are copy number variants?
Changes in number of whole or parts of chromosomes
Name a trisomy associated with CHD?
Downs syndrome (trisomy 21) - AV septal defects and duodenal atresia
Name a monosomy associated with CHD?
Turners (45, x) - coarctation of aorta, AS, bicuspid aortic valve
Name some micro deletions associated with CHD
22q11 deletion - cardiac malformation
Williams syndrom - supravalvular AS
Name some single gene defects that cause CHD
Noonan/Cardio-facio-cutaneous syndrome Marfans Leopord syndrome Costello syndrome Holt-Oram Fanconi CHARGE
Name some teratogens known to cause CHD
Rubella
Alcohol
Anti-epileptic drugs
Maternal DM
What causes trisomy 21?
Mostly maternal non-disjunction (95%)
Translocation (3%)
Mosaic (2%)
What is nuchal translucency used for?
Collection of fluid under skin at back of babies neck, measured with ultrasound at around 12 weeks.
This is increased in babies with Downs and those with CHD
How do we test for Downs syndrome in babies?
Nuchal translucency
Blood tests for hCG and PAPP-A
All increased in downs, and if positive they are sent for amniocentesis or chorionic villus sampling
What is associated with CHD and abnormal chromosomes in newborns?
Cystic hygroma - congenital multiloculated lympathic lesions, usually located in left posterior triangle of neck and armpits
Name signs of Turners syndrome
Short stature Wide set nipples Broad chest Low set ears Gonadal dysgenesis Reproductive sterility Puffy hands and feet due to lymphedema CHD - coarctation, AS, bicuspid AV
What is somatic mosaicism?
It describes the presence of two or more populations of cells with different genotypes in one individual, which may only affect a portion of the body and is not transmitted to progeny
What is neck webbing?
Caused by excessive nuchal folds and cystic hygroma during development
What CHDs can cause neck webbing?
Turners Noonan syndrome Cardio-facio-cutaneous syndrome Leopord syndrome Costello syndrome
Name 3 Noonan like syndromes
Cardio-facial-cutaneous syndrome - plus ectodermal problems and developmental delay
Leopord syndrome - plus multiple lentigenes and deafness
Costello syndrome - plus thickened skin folds, susceptible to warts, cardiomyopathy and cancer risk later in life
Describe the physical characteristics of Noonans syndrome
Pulmonary stenosis
Short
Neck webbing
Cryptorchidism (loss of one or more testes)
Characteristic face (wide eyes, deep philtre, short broad nose)
What gene is responsible for Noonan syndrome, and Noonan like syndromes?
PTPN11 mutation in chromosome 12, autosomal dominant, causing mutations in MAPK pathway
What are the signs for 22q11.2 deletion syndrome?
CATCH 22
Cardiac malformation Abnormal facies e.g. floppy ears, bulbous nose, cleft lip, long face, hooded eyelids Thymic hypoplasia Cleft palate Hypoparathyroidism 22q11 deletion
also have asymmetric crying face
How can 22q11.2 deletion syndrome present later in life?
Renal impairment
Psychiatric - schizophrenia, depression, bipolar
What 2 syndromes are referred to as 22q11.2 deletion syndrome?
DiGeorge syndrome
- thymic hypoplasia
- hypoparathyroidism
- outflow tract cardiac malformation
- usually sporadic
Shprintzen syndrome
- cleft palate/palatal insufficiency
- outflow tract cardiac malformation
- characteristic face
- autosomal dominant
Describe the signs of Williams syndrome
Supravalvular aortic stenosis Murmurs and narrowing of vessels Hypercalcaemia 5th finger clinodactyly "Elfin" face - broad forehead, short nose, full cheeks, widely spaced teeth, long philtrum Mild to moderate intellectual disability Cocktail party manner/behaviour Failure to thrive Poor muscle tone
What causes Williams syndrome?
Deletion of elastin gene and neighbouring genes on chromosome 7
What features are seen in babies damaged by alcohol consumption while mother was pregnant?
Intrauterine growth retardation Head circumference <10th percentile Thin upper lip Shorter distance between eyes Motor and visual impairment Hearing loss ADHD
What does Rubella infection during pregnancy cause the baby?
Cardiac defects e.g. patent ductus arteriosus
Cerebral defects
Ophthalmic defects
Auditory defects
What congenital cardiac affects are caused by maternal diabetes?
Transposition of the great vessels Ventricular septal defects Atrial septal defects Coarctation of the aorta Cardiomyopathy Single umbilical artery
What features are seen in babies damaged by anti-epileptic drugs consumption while mother was pregnant?
Cardiac defects Hypospadias Oro-facial clefts Hypertelorism (increased distance between eyes) Flat nasal ridge low set ears microcephaly short neck hypoplasia of phalanges and nails Cognitive and behavioural disturbances Intrauterine growth retardation
Name some CV connective tissue diseases
Marfans syndrome
Loeys-Dietz syndrome
Ehlers Danlos
Familial thoracic aortic aneurysms
Name some familial arrhythmias
Long QT
Brugada
CPVT
Arrhythmogenic RV cardiomyopathy
Name some familial cardiomyopathies
Hereditary cardiomyopathy
Dilated cardiomyopathy
Describe the genetics of Marfans syndrome
Autosomal dominant deletion of the fibrillin 1 gene on chromosome 15q21
Also some mutations in TGFbR (chr3) gene
Describe the physical features of those with Marfans syndrome
Tall, thin, long arms and legs Arachnodactyly Sternal depression Flexible joints Scoliosis Upwards lens dislocation Protrusio acetabula (displacement of femoral head in hip joint)
What cardiac conditions are associated with Marfans syndrome?
Mitral valve prolapse
Aneurysms (particularly in ascending aorta)
Aortic valve incompotence
How is Marfans diagnosed?
Ghent criteria - need 2 positive major criteria and >7 minor criteria
What counts as major criteria in Ghent criteria for Marfans?
CV - aortic dilatation/dissection
Eyes - ectopic lentis
Family history
Fibrillin mutation (NOT deletion)
What counts as system criteria in Ghent criteria for Marfans?
Skeletal - scoliosis/kyphosis, pectus deformity
Skin - striae
Resp - pneumothorax, apical blebs on CXR
Dural ectasia (widening of dura around spinal cord)
CV - MVP
Myopia (short sighted)
Who should receive a genetic test for Marfans?
Those with any single major feature
Systemic score >7
Possible family history
Increased aortic diameter
How do you test for Marfans?
Genetic test for fibrillin mutation
ECHO
MRI/pelvic X-ray - dural ectasia and protrusio acetabula etc
What treatment is offered to Marfans syndrome sufferers?
annual review with ECHO of aortic root
beta blockers and ARBs slows dilatation
Prophylactic aortic surgery if dilated
TGFb antagonist Losartan (mouse model)
When is prophylactic aortic surgery offered to those with Marfans?
Diameter = 5.5cm
If grows by 5% in one year (2mm in adults)
What are some Marfan like syndromes?
Loeys-Dietz syndrome
Ehlers Danlos
Familial thoracic aortic aneurysms
Describe Loeys-Dietz syndrome
Chromosome 3p22/9q33 (TGFbR) Arterial dissection Tortuosity Bifid uvula/cleft palate Hypertelorism (increased distance eyes) Skin and skeletal findings
Describe the genetics of familial thoracic aortic aneurysms
Chr 11q and 5q, though genes unknown
What is the major variants of long QT syndrome?
Romano-Ward syndrome
Jervell Lange-Neilson syndrome
Describe signs of long QT syndrome on ECGs
Torsades de Pointes Long QT interval (>0.42 sec) Repolarization anomalies (T/U waves)
What is long QT syndrome?
Rare congenital or acquired condition, where the prolonged repolarisation period increases the risks of episodes of Torsades de Pointes (“party streamer”), a form of irregular heartbeat that originates from the ventricles and can lead to sudden cardiac death
What can stimulate Torsades de Pointes?
Emotion
Exercise
Drugs
Describe the symptoms of long QT syndrome
Syncope
Seizures
Sudden death due to VF
What can be used to determine the genotype of long QT syndrome?
Different T wave patterns
Precipitants of arrhythmia
How is long QT treated?
Genetic screening Beta blockers and vasodilators (nicorandil) Na channel blockers Anti-arrhythmics ICDs
What syndromes are linked to increased risk of sudden cardiac death?
Long QT syndrome
Braguda syndrome
Hypertrophic cardiomyopathy
Arrhythmogenic RV cardiomyopathy
Describe Braguda syndrome
Persistent ST elevations in leads V1-3 with right bundle branch block, with an increased risk of sudden cardiac death due to VT/VF
What is the leading cause of sudden cardiac death in young athletes?
Hypertrophic cardiomyopathy
Describe the histology of cardioymopathy
Disordered cardiac myocytes cause arrhythmia
Truncation of titin in DCM
Describe arrhythmogenic RV cardiomyopathy
Effort induced polymorphic tachycardia (LBBB) due to A.D. mutations in cell junction genes. This leads to thinning of the ventricular wall, meaning the heat doesn’t pump effectively, and electrical impulses are interrupted due to damage to the normal pathway = arrhythmias and sudden cardiac death
What is cascade sequencing?
When an individual is found to have an abnormal ECG, 3 gen FH of first degree relatives is taken. ECGs are also carried out for all available, as well as next gen sequencing.
