Genetics Flashcards
What is penetrance?
The likelihood of having a disease if you have a gene mutation
100% penetrance means you will always get the disease if you have the mutation
What can an exonic mutation result in?
Change of amino acid sequence
Create stop codon
Frameshift
No effect
Are intronic variants commonly pathogenic?
No
In describing mutations, how is a stop codon symbolised?
*
What is the cDNA?
Mature mRNA sequence with the introns removed, referenced to the first base of the first codon
What mutation results in marfan syndrome?
Fibrillin mutation
What causes Loeys dietz Syndrome and what are some classical features?
Mutation sin TBR1 or TBR2
Bifid uvula
Widely spaced eyes
Tortuous blood vessels
What mutations result in romano-ward (AD) syndrome?
LQTS mutations
How is familial hypercholesterolemia diagnosed?
Total cholesterol >7.5 mmol/L or LDL cholesterol >4.9 mmol/L in adults
Tendon xanthomas
DNA based evidence of a mutation in LDLR, APOB or PCSK9
FMHx of premature MI (<50 yrs)
FMHx of elevated total cholesterol >7.5 mmol/L
What are the incidences of “rare” genetic cardiac disease?
Marfans; 1 in 5000
Long QT; 1 in 2000
HOCM 1 in 500
Familial hypercholesterolemia 1 in 500
What are the common channelopathies that can lead to sudden death?
Long QT syndrome
Brugada Syndrome
Short QT syndrome
Catecholaminergic polymorphic ventricular tachycardia
Describe catecholaminergic polymorphic ventricular tachycardia (CPVT)?
AD mutation in gene encoding for cardiac ryanodine receptor (RYR2) the main intracellular calcium release channel of cardiomyocytes
What are the ECG findings of brugada syndrome?
RBBB
Persistent ST elevation in leads V1-3
Normal QT intervals
What is the genetics behind brugada syndrome?
Mutation of cardiac sodium channel SCN5A
AD
What drugs should be avoided in brugada syndrome?
Antiarrhythmic drugs - specifically class 1
Psychotropic drugs, TCA, lithium, antipsychotics,
Anaesthetics/ analgesics; bupivacaine, procaine, propofol
Excessive alcohol
Cannabis
Cocaine
What is the danger with long QT syndrome?
Prolonged QT intervals and/or polymorphic U waves are assoc with torsades de pointes and subsequent deterioration to VF
What investigations are recommended for screening for inherited cardiac issues?
12 lead ECG
Echo
Holter monitor
Cardio-pulmonary exercise ECG test
What is the most common genetic cardiac disease?
HOCM
What are the characteristics and diagnostic features of HOCM?
Marked and asymmetric left ventricular hypertrophy
Left ventricular outflow obstruction at rest caused by mitral-septal contact during systole
LV wall thickness >13mm
What are symptoms of HOCM?
Chest pain
Dyspnoea
Palpitations
Syncope
What are the treatments available for HOCM?
ICD
Beta blockers, verapamil
Surgical myectomy
What are the genetic features of HOCM?
AD with incomplete penetrance
4 loci;
Beta myosin heavy chain on chromosome 14 (30%)
Alpha-tropomyosin on chromosome 15 (3%)
Cardiac troponin T on chromosome 1 (15%)
Locus on chromosome 11
Can you give digoxin in AF with co-existing HOCM?
No
Describe arrhythmogenic right ventricular cardiomyopathy
Rare cause of dilated cardiomyopathy in which there is gradual replacement of the myocardium of RV with fibroadipose tissue
What can cause dilated cardiomyopathy?
Familial Coronary artery disease Valvular heart disease Hypothyroidism Thyrotoxicosis Haemochromatosis Collagen vascular disorders Alcohol or drug related heart muscle disease
What are the ecg changes seen in RBBB?
Best seen in V1 with an rSr pattern QRS duration >120 ms Dominant R in V1 Inverted T waves in V1-3 or V4 Wide and deep S in V6
What are the ecg changes seen in LBBB?
Q wave in V1 and an R wave in V6
Best seen in V6 with an M pattern
Deep and wide S wave in V1
