Genetics and cardiovascular disease 1 Flashcards
What is the pathology of congenital Heart disease?
Variations depending on which genes and how the genes have been affected.
Eg abnormalities include:
- patent ductus arteriosus
- aortic stenosis
- coarction of the aorta
- atrial septal defect
- ventricular septal defect
- pulmonary stenosis
- tetralogy of Fallot
Give examples of single nucleotide variation gene syndromes
Mendelian disorders eg Noonan, Marfan, SVAS, Holt-Oram
EG chromosomal syndromes part and whole
WHole chromosome (trisomy, monosomy): -downs (trisomy 21), turners (45X)
Partial chromosome eg 22q11 deletion, Williams
EG microdeletion syndromes
22q11, Williams,
Why is a genetic diagnosis relevent to treatment? How can the diagnoses affect the treatment?
Because depending on the genetic varitation it may effect what the patient is susceptiable to and what they are likely to develop, when their symptoms start etc so tht you can taylor the treatment as best as you can to have the best outcomes for the patient.
After a genetic diagnosis, how is family planning managed?
If positive for the disease, may be that you then test immediate relatives eg siblings in marfan syndrome.
Give examples of association gene abnormalities
common combination of ffeatures, but varying causes.
CHARGE and VACTERL
Charge = Coloboma, Heart defects, atresia of choamae, retardation of growth, Genital and Ear abnormalities
VACTERL = Vertebral annomalies, Anal-rectal atresia, cardiac defects, tracheaesophageal fistutula, renal and Limb abnormalities.
WHat is a mltifactorial chd
usually causes iusolated congenital heart disease, with no associated features, usually due to interaction of many different types of genes and potentiallly the enironment
WHat is the genetic abnormality in down syndrome? WHat is the most common heart defect? What is another issue?
Trisomy 21 95% maternal non disjunction, 3% translocation and 2% mosaic
Most common heart defect is atrio-ventricular septal defect (affecting 15%)
Another common issue is duodenal atresia (closed off duodneal)
What is nuchal translucency a sign of?
Several genetic disorders inc. Downs syndrowme, turner 45X.
Its like a fluidy space behind the head of the foetus and can be seen at 12 weeks.
What happens in Turner Syndrome?
There is only one X (not XX or XY). Can be mosaic, meaning that they can have both cells with 45X and 46XY, typically at a higher risk of gonadal malignancy.
What are the heart complications of turner syndrome?
Coarctation of the aorta
Ouffiness on backs of hands and backs of feet is a sign of what in a baaby?
Turner syndorome
Neck webbing is a sign of what?
increased nuchal translucency as a foetus - can be an indicator of preantal cardiac difficulties, which is seen in a varitey of single gene disorders as well as turners and downs, inc. noonan and cardiofaciocutaneous, leopard and costello.
What is noonan syndrome due to?
Single nucleotide varation of PTPN11 gene.
What genes do we test when noonan like syndrome? And what common cardiac abnormalities may they have? Also give examples of conditions that are noonan like
Gene tested are the MAPK pathway genes (as most of the syndromes have an abnormality in one of the genes that affects the pathway.
Common cardiac abnormalities include pulmonary stenosis.
Conditions include Noonan syndrome, Cardio-Facio-Cutaneous (CFC), Leopard and Costello syndrome
What is 22q11 deletion syndrome? What are the differences DiGeorfe and Shprintzen
CATCH22 (but can’t say that to the patient.
- Cardiac malformation
- Abnormal faces
- Thymic hyperplasia
- Cleft palate
- Hypoparathyroidism
- 22q11 deletion
Digeorge and Shprintzen are both 22q11 deletion syndromes, DiGeorge is is de-novo and Shprintzen is familiar
Why would you consider testing for 22q11 deletin syndrome in schizophrenia ?
Because 22% adult 22q11 deletions have schizophrenia (v common), 2% all patients with schizophrenia have 22q11 deletion
WHAT IS wILLIAMS syndrome? What is the heart abnormalities?
Caused by deletion of continuous genes (elastin on chromosome 7)
Causes aortic stenosis (supravalvular), and can cause hypercalcemia.
What is fetal alcohol syndrome? What are other causes of teratogen genetic diseases
think upper lip, wide eyes, adhd
Other causes inc. Antiepilectic drugs (sodium valproate), rubella, maternal diabetes mellitus
Cardiac abnormalities in isolation, more liekly to be passed on to child if mother or father has it?
More likely if mother has the abnormality than if the father has the abnormality.
What effect doe folic acid have? How about MTHFR or multivitamins?
MTHR gene impairs folate metabolism. If folic acid intake is low and folate lvels low, baby more likely to develop congenital heart disease.
Likewise, Mothers on periconceptual vitamins are more likely to have a child without congenital abnormality.
EG cardio connective tissue diseases
Marfan, Loeys-Dietz, Vascular Ehlers Danlos, FTAA (Familial thoracic aortic aneurysm)
Are all the eHLER- ALL THE SAME
Nope, vascular Ehlers Danlos is generally much more severe compared to the other types.
What is MarfAN syndrome? Where is the mutation? What are the clinical overlaps ?
It is an autosomal dominant genetic disorder usually of the gene for fibrillin 1 gene, which is on chromosome 15 - 15q21.
Clinical overlaps fairly closely with loeys-dietz syndrome and vascular ehlers Danlos syndrome
How do you diagnose Marfans?
You need at least 2 of the following: (it cna be v hard to diagnose and often you will have to do all the specific testing to find 2 points)
- Cardiovascular system (aortic dilatiation/dissection)
- Eyes (Ectopia lentis - dislocated lense, can cause iridodenesis - shaky iris)
- Family history - definite relative has it
- Fibrillin1 mutation
- Systemic score greater than 7 (see below)
- wrist and thumb sign (3 points)
- pectus carinatum deformity (2, chest asymmetry or pectus excavatum score 1)
- hindfoot deformity (2) flat foot (1)
- pneumothorax (1)
- Dural Ectasia (2) - swelling at bottom of dural sac
- protrusio acetabuli (hip in too far) (1)
- Reduced US/LS AND increased arm/height AND no severe scoliosis (1)
- Scoliosis or thoracolumbar kyphosis (1)
- Reduced Ebbow extension
- Facial features 3/5- (1)
- skin striae (1)
- Myopia (short sightedness) (1)
- Mitral Valve prolapse (1)
What is iredodenesis?
When the iris flaps about like a pair of curtains when moving eye around. Usually becuase the lense has become detatched at the back and this counts as a 1/2 criteria needde to diagnose marfans
How is marfans managed?
At least annual clinical review (in. echocardiogram)
Pharmacological management: b blockers, Angiotensin II Receptor Blockers
Prophyllactic aortic surgery if sinus of Valsalva exceeds 5.5 cm or 5% growth per year (2 mm in adults)
Monitor aortic root frequently in pregnancy if diameter exceeds 4cm
What surgical options are there for marfan aortic root?
Take out and replace with or without mechanical valve.
Newer treatment option of using scan to measure aorta and create custamised aortic root support if aorta not too big
What is Sudden Unexpected death?
Unexpected death (no previous conditions) aged 1-40.
Most of the time thought to be due to arrythmia. 40-53% shown to have identifiable inherrited heart disease. Thought 35% had ion channelopathy - most causing long QT syndrome.
What is long QT syndrome? Symptoms
AN increased length of time between the start of depolarisation and the end of repolarisation (time vents are depolarised). Causes Romano-Ward syndrome and Jervell Lange-Neilsen (RW with congenital deafness).
Symptoms include:
- Syncope,
- “seizure”
- sudden death
Can be brought on/exacerbated with drugs, strong emotions or exercise
How do you calculate the qt length for the heart rate?
Using BAzetts formulae
What is Jervell Lange-Neilsen syndrome?
Long QT syndrome with congenital deafness
LQT 1 LQT2 LQT3 caused by? What %? How effected?
Different sections of the genes:
LQT1: K channel gene: KCNQ1 40%
LQT2: K channel gene KCNH2 40%
LQT3:sodium channel gene, SCN5A 10%
10% = other (mainly K channel genes tho)
K channel changes causes delays in repolarisation of myocyte
Na channel gene changes causes change and slowing down of the depolarisation of the myocytes
What drugs can cause long QT?
Antibiotics, anti psychotics and can be secondary to cardiomyopathies
What are the treatment options for gnenotypes?
LQT1: K channel gene: KCNQ1 usually brought on by Exercise, particularly swimming. ECG is Normal/broad
LQT2: K channel gene KCNH2 usually brought on by loud noises, notched ECG
LQT3:sodium channel gene, SCN5A brough on by Sleep bradycardia ecg Biphasic
What is Brugada syndrome?
Simelar to long QT symptoms and changes to SCN5A gene (more common over night)
Saddleback/covered ECG.
More common in far east.
If unsure, (ECG may not always clearly show) can diagnose it by doing an Ajmaline challenge test. Ajmaline is a sodium channel blocker, which will bring out the ECG features in an affected person. Need to be resuss ready.
Brugade type 1 vs 2 and 3. More common where? If ecg normal then what investifation? How is it managed?
Avoiding fever, alcohol and excessive food (bradycardia effects). And ICD may be implanted.
MOst common in the far east eg Thailand
Type 1 is most significant, if ecg normal but have suspician, then Amjamaline challange may be used.
What is ARVC?
Arrhythmogenic right ventricular cardiomyopathy
Fat and fibrosis in the right ventricle so it doesn;t work properly.
Excercise related arrhythmia and looks like left bundle branch block
Genetic gene in the cell junction mechanism.
What is Hypertrophic Cardiomyopathy? What genes cause these?
Most common genetic heart disease
Increase in heart muscle/tissue, so reduced vol, and disarrayed tissue can cause arrhythmias
Due to genes inc. MYBPC3, MYH7
What causes dilated cardiac myopathy?
Often caused by changes to the titan gene.
Can be related to pregnancy and alchoholism
What do you need to exclude when considering dilated cardiomyopathy?
Ischaemic heart disease (angiography)
Hypertension
Skeletal muscle disease (neurology/genetics evaluation, CPK)
Alcohol abuse (history and biochemical evidence, but 9% have TTN mutation)
Exposure to cardiotoxic drugs (history)
Haemochromatosis (ferritin/genotyping)
Sanger vs next generation sequencing
Next gen (massively parallel sequencing) can sequence V large amounts of the genome
Sanger sequences can only sequence short sections of DNA
What does it mean by nonsense, missense, splucing, inframe deletion?
Nonsense = non = amino acid changed to stop codon eg CF
Missense= different amino acid in protein
Splicing =to do with exons and introns when the introns get spliced out
Inframe = reading frame resereved but one amino acid is delelted
