Genetics and cardiovascular disease 1

Question 1

What is the pathology of congenital Heart disease?

Answer 1

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

Question 2

Give examples of single nucleotide variation gene syndromes

Answer 2

Mendelian disorders eg Noonan, Marfan, SVAS, Holt-Oram

Question 3

EG chromosomal syndromes part and whole

Answer 3

WHole chromosome (trisomy, monosomy):
-downs (trisomy 21), turners (45X)

Partial chromosome eg 22q11 deletion, Williams

Question 4

EG microdeletion syndromes

Answer 4

22q11, Williams,

Question 5

Why is a genetic diagnosis relevent to treatment? How can the diagnoses affect the treatment?

Answer 5

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.

Question 6

After a genetic diagnosis, how is family planning managed?

Answer 6

If positive for the disease, may be that you then test immediate relatives eg siblings in marfan syndrome.

Question 7

Give examples of association gene abnormalities

Answer 7

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.

Question 8

WHat is a mltifactorial chd

Answer 8

usually causes iusolated congenital heart disease, with no associated features, usually due to interaction of many different types of genes and potentiallly the enironment

Question 9

WHat is the genetic abnormality in down syndrome? WHat is the most common heart defect? What is another issue?

Answer 9

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)

Question 10

What is nuchal translucency a sign of?

Answer 10

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.

Question 11

What happens in Turner Syndrome?

Answer 11

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.

Question 12

What are the heart complications of turner syndrome?

Answer 12

Coarctation of the aorta

Question 13

Ouffiness on backs of hands and backs of feet is a sign of what in a baaby?

Answer 13

Turner syndorome

Question 14

Neck webbing is a sign of what?

Answer 14

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.

Question 15

What is noonan syndrome due to?

Answer 15

Single nucleotide varation of PTPN11 gene.

Question 16

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

Answer 16

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

Question 17

What is 22q11 deletion syndrome? What are the differences DiGeorfe and Shprintzen

Answer 17

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

Question 18

Why would you consider testing for 22q11 deletin syndrome in schizophrenia ?

Answer 18

Because 22% adult 22q11 deletions have schizophrenia (v common), 2% all patients with schizophrenia have 22q11 deletion

Question 19

WHAT IS wILLIAMS syndrome? What is the heart abnormalities?

Answer 19

Caused by deletion of continuous genes (elastin on chromosome 7)

Causes aortic stenosis (supravalvular), and can cause hypercalcemia.

Question 20

What is fetal alcohol syndrome? What are other causes of teratogen genetic diseases

Answer 20

think upper lip, wide eyes, adhd

Other causes inc. Antiepilectic drugs (sodium valproate), rubella, maternal diabetes mellitus

Question 21

Cardiac abnormalities in isolation, more liekly to be passed on to child if mother or father has it?

Answer 21

More likely if mother has the abnormality than if the father has the abnormality.

Question 22

What effect doe folic acid have? How about MTHFR or multivitamins?

Answer 22

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.

Question 23

EG cardio connective tissue diseases

Answer 23

Marfan, Loeys-Dietz, Vascular Ehlers Danlos, FTAA (Familial thoracic aortic aneurysm)

Question 24

Are all the eHLER- ALL THE SAME

Answer 24

Nope, vascular Ehlers Danlos is generally much more severe compared to the other types.

Question 25

What is MarfAN syndrome? Where is the mutation? What are the clinical overlaps ?

Answer 25

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

Question 26

How do you diagnose Marfans?

Answer 26

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)

Question 27

What is iredodenesis?

Answer 27

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

Question 28

How is marfans managed?

Answer 28

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

Question 29

What surgical options are there for marfan aortic root?

Answer 29

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

Question 30

What is Sudden Unexpected death?

Answer 30

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.

Question 31

What is long QT syndrome? Symptoms

Answer 31

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

Question 32

How do you calculate the qt length for the heart rate?

Answer 32

Using BAzetts formulae

Question 33

What is Jervell Lange-Neilsen syndrome?

Answer 33

Long QT syndrome with congenital deafness

Question 34

LQT 1 LQT2 LQT3 caused by? What %? How effected?

Answer 34

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

Question 35

What drugs can cause long QT?

Answer 35

Antibiotics, anti psychotics and can be secondary to cardiomyopathies

Question 36

What are the treatment options for gnenotypes?

Answer 36

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

Question 37

What is Brugada syndrome?

Answer 37

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.

Question 38

Brugade type 1 vs 2 and 3. More common where? If ecg normal then what investifation? How is it managed?

Answer 38

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.

Question 39

What is ARVC?

Answer 39

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.

Question 40

What is Hypertrophic Cardiomyopathy? What genes cause these?

Answer 40

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

Question 41

What causes dilated cardiac myopathy?

Answer 41

Often caused by changes to the titan gene.

Can be related to pregnancy and alchoholism

Question 42

What do you need to exclude when considering dilated cardiomyopathy?

Answer 42

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)

Question 43

Sanger vs next generation sequencing

Answer 43

Next gen (massively parallel sequencing) can sequence V large amounts of the genome

Sanger sequences can only sequence short sections of DNA

Question 44

What does it mean by nonsense, missense, splucing, inframe deletion?

Answer 44

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