Genetic heart disease

Question 1

types of genetic cardiac disease

Answer 1

cardiovascular connective tissue disease, familial arrhythmias, familial cardiomyopathy

Question 2

cardiovascular connective tissue diseases

Answer 2

marfan, loeys Dietz, vascular ehlers-danolos, syndromic, non-syndromic familial thoracic aortic aneurysms

Question 3

marfan syndrome

Answer 3

autosomal dominant, multisystem, connective tissue, mutation on the fibrillar 1 gene on chromosome 15, clinically overlaps with joeys dietz syndrome, other aortopathies and some forms of EDS. difficult to diagnose, needs too positive findings, features show over time

Question 4

Ghent nosology

Answer 4

diagnosis of Marfan rests on two positive findings on 5 sections- CVS eg aortic dilatation/dissection, eyes, systemic score more than 7, unequivocally affected relative, mutation that causes MFS

Question 5

iridodenesis

Answer 5

feature of marfans, shaking iris

Question 6

marfans clinical assessment

Answer 6

Ghent 2010 features, arrange echo to measure diameter of sinus of Valsalva, x ray for protrusio, MRI for dural extasia, undertake genetic testing

Question 7

losartan

Answer 7

TGF beta antagonist ( TGF beta affects cell proliferation, differentiation and apoptosis. those deficient in fibrillar have excess TGFbeta and marfan features)

Question 8

medical management of marfan

Answer 8

aortic stiffness and risk of rupture increases with aortic diameter so management aims to reduce diameter, control BP, surgical intervention if risk of rupture is too high. at least annual clinical review- echo, B blockers, angiotensin II receptor blockers, prphylactic aortic surgery if sinus of Valsalva exceeds 5.5cm or 5% great per year, monitor aortic root frequently in pregnancy if diameter exceeds 4cm

Question 9

surgical intervention for marfans syndrome

Answer 9

aortic root surgery- mechanical valve (lasts longer but needs anticoagulant), valve sparing procedure (may need reoperation but no anticoagulant), use of Dacron to go around aorta

Question 10

long QT syndrome- romano-ward syndrome.

Answer 10

autosomal dominant. syncope, seizure, sudden death, triggered by emotion, exercise drugs.ECG shows prolonged QTc interval, depolarisation anomalies, paroxysmal polymorphic VT

Question 11

long QT syndrome- Jerrell lange-neilsen

Answer 11

autosomal recessive. syncope, seizure, sudden death, triggered by emotion, exercise drugs.ECG shows prolonged QTc interval, depolarisation anomalies, paroxysmal polymorphic VT and congenital sensorineural deafness

Question 12

long QT 1 are caused by

Answer 12

changes in the potassium channel genes

Question 13

long QT 2 are caused by

Answer 13

changes in the potassium channels genes

Question 14

long QT 3 are caused by

Answer 14

changes in sodium channel genes

Question 15

why do long QT intervals cause ventricular tachycardia

Answer 15

another wave of depolarisation comes before the cells are fully recovered from the previous one

Question 16

genotype mutation prediction if exercise particularlt swimming exacerbates it

Answer 16

normal/ broad T wave, KCNQ1

Question 17

genotype mutation prediction if noise or arousal exacerbates it

Answer 17

notched t wave, KCNH2

Question 18

genotype mutation prediction if sleep or bradycardia exacerbates it

Answer 18

biphasic t wave, SCN5A

Question 19

brugada syndrome

Answer 19

arrhythmia disorder, syncope, seizure , sudden death, usually a SCN5A disorder, occurs more in young men in Far East arrhythmia occurs during sleep, avoid excess alcohol, fever, overeating for management, can get an implanted cardiac defibrillator

Question 20

ARVC

Answer 20

arrhythmia disorder, Rv dyskinesia which is shown on MRI or echo, epsilon waves and T wave inversion which I shown on ECG, late potentials, effort induced VT, fatty infiltration of right ventricle, family history or pathogenic gene variant

Question 21

hypertrophic cardiomyopathy sarcomere disease

Answer 21

heart muscle is thickened and enlarged, common but mild and doesn’t develop symptoms until later in life, usually caused by mutation in MYBPC3 and MYH7, causes arrythmia, ventricular tachycardia

Question 22

titan truncating variants

Answer 22

Titin is the largest human protein and a crucial component of all striated muscle, in which it has structural, sensory, and signaling functions. TTNs account for 10% of all dilated cardiomyopathy, 25% of familial dilated cardiomyopathy, 10% of apparently alcoholic DCM, 10% of pregnancy associated DCM, variable penetrance and can act as a susceptibility factor in some cases

Question 23

dilated cardiomyopathy management

Answer 23

first rule out conditions before doing genetic testing so do test to find if ischaemic heart disease, hypertension, skeletal muscle disease, alcohol abuse, exposure to cardio toxic drugs, haemochromatosis, mitochondrial disorder, family history of cardiomyopathy, genetic testing last for TTN, LMNA, MYH7, MYBPC3 etc

Question 24

massively parallel sequencing

Answer 24

enables to test massive parts of the genome, long runs of DNA, do gene panels, whole exome and whole genome, the more genes you sequence the more variants you find

Question 25

categories for pathogenicity of variants

Answer 25

pathogenic, likely pathogenic, uncertain, likely benign, benign

Question 26

what to look at when classifying pathogenicity of variants

Answer 26

is it nonsense, missesnse, splicing, deletion, promotor, regulatory
VEP software
literature reports
phenotype match
variant frequency in apparent normal population
segregation in family
de novo or not