Genetics of CVD - Ting Flashcards
What is the main histological feature of HCM? Why do we see it?
Myofiber disarray
It’s caused by mutations in the sarcomere proteins
Why is the presentation of HCM variable?
There are multiple possible sarcomere mutations; they can present very differently.
What is the “classic” mutation in HCM?
MYH7
How does HCM classically present?
patient is 30-50, presenting with exercise intolerance, shortness of breath, etc.
They will have LVH without hypertension or aortic stenosis. They may have an arrhythmia as well.
How is HCM inherited?
Autosomal dominant inheritance, but can arise sporadically
How is DCM inherited?
Mostly autosomal dominant inheritance, but can be X-linked, autosomal recessive, or mitochondrial
What is the LMNA mutation?
An especially potent mutation that can lead to DCM
demonstrates pleiotrophy in that it also causes muscular dystrophy, neuropathy, arrhythmias, lipodystrophy, and progeria
Who should be clinically screened for cardiomyopathy?
Asymptomatic first degree relatives
Relatives known to carry the mutation
How often should clinical screening take place in patients with a KNOWN mutation?
Yearly during childhood, every 3 years after
EXCEPT ARVD, which is yearly after age 10 (it takes time for this mutation to present)
How does familial hypercholesterolemia clincally present?
May present asymptomatic and be found with routine cholesterol screening (less common)
xanthomas
How is familial hypercholesterolemia inherited? Why is this important?
Can be autosomal dominant or recessive
Recessive disease is homozygotic and presents earlier and more severely
What mutations cause FH?
LDLR (60-80%)
APOB (1-5%)
PCSK9 (3-?%)
Why is genetic testing required for FH?
Homozygotes will not respond to just one therapy; multiple, aggressive therapies are needed
Starting from a proband, name the degree of relative for each of the following:
1) Parent
2) Grandparent
3) Child
4) Great Aunt/Great Uncle
5) Grandchild
6) First cousin
7) Aunt/Uncle
8) Niece/Nephew
9) Brother/Sister
1) Parent - 1st
2) Grandparent - 2nd
3) Child - 1st
4) Great Aunt/Great Uncle - 3rd
5) Grandchild - 2nd
6) First cousin - 3rd
7) Aunt/Uncle - 2nd
8) Niece/Nephew - 2nd
9) Brother/Sister - 1st
For an X-linked recessive inheritance pattern, a CARRIER mother has a _____% chance of having an AFFECTED son and a _____% chance of having a CARRIER daughter.
50%, 50%
Describe the difference between REDUCED PENETRANCE and VARIABLE EXPRESSIVITY.
Reduced Penetrance: Less than 100% of individuals with a given genotype actually express signs of symptoms
Variable expressivity: Signs and symptoms of a genetic condition DIFFER between affected inviduals
Describe the difference between GENETIC HETEROGENEITY and PLEIOTROPY.
Genetic Heterogeneity: A genetic disorder can be caused by a mutation in more than one allele
Pleiotropy: Genetic variants in a single allele can cause several seemingly unrelated signs or symptoms
(In short: Heterogeneity = many possible mutations, one disease. Pleiotropy = one mutation, many possible diseases/symptoms)
Long QT Syndrome:
1) What is the name of a major variant of this syndrome?
2) Aside from syncope and SCD, name another possible consequence?
3) When does syncope tend to occur?
1) Romano Ward Syndrome
2) Seizures
3) During exercise or high emotions
Romano Ward Syndrome:
1) What is the inheritance pattern?
2) What are the three most commonly mutated genes?
1) Auto Dominant with reduced penetrance (50%) and pleiotropy (10 genes associated)
2) KCNQ1, KCHN2, SCN5A (these are also the most commonly mutated genes in all LQTS types as a whole, representing types LQTS1, LQTS2, and LQTS3, respectively)
What types of LQTS show increased risk of tachyarrhythmias (and SCD) during sleep?
LQTS2, LQTS3, LQTS6, & LQTS9.
Name four ways LQTS can be treated / managed.
1) Beta-blockers
2) Pacemakers
3) Defibrillator access
4) Implantable cardioverter-defibrillators (ICDs)
1) What named subtype of LQTS also presents with congenital, profound, bilateral sensorineural deafness?
2) What is this syndrome’s inheritance pattern?
3) What two genes are associated with this?
1) Jervell & Lange-Nielson Syndrome (JLNS)
2) Auto recessive
3) KCNQ1 (LQTS1), KCNE1 (LQTS5)
(It seems like one mutated copy of these genes gives LQTS (Auto Dominant), whereas two mutated copies gives the more serious JLNS (Auto Recessive)?)
What is the current genetic testing detection rate for LQTS? What does this mean?
75%. This means that 25% of families with clinical LQTS do NOT have a detectable/known gene mutation.
(Other presentations include: some pts have large genomic rearrangements. Some pts have TWO known mutations.)
Brugada Syndome:
1) What is the major problem?
2) What ECG abnormalities can be seen? In what leads?
3) What is a major gene that is believed to lead to Brugada Syndrome when mutated?
Brugada Syndrome:
1) Conduction abnormalities that cause high risk for Vent. arrhythmias, leading to syncope, SIDS, or SUNDS (sudden nocturnal death)
2) ST-segment elevation in right precordial leads (V1-V3)
3) SCN5A (alpha subunit of cardiac sodium channel)
CPVT:
1) What does it stand for?
2) How can it kill you?
3) What sub-lethal consequence of CPVT is also seen in some types of LQTS?
1) Catecholaminergic Polymorphic Ventricular Tachycardia
2) Bidirectional or Polymorphic Vent Tachy that degenerates into Vfib. This kills the person.
3) Syncope brought on by exercise / acute emotion
CPVT:
Mutations in one of two genes result in the majority of cases. Name both genes, their functions, and their inheritance patterns.
1) RYR2. Cardiac Ryanodine receptor channel. Autosomal dominant. 2) CASQ2. Calsequestrin - a Ca2+ buffering protein of the SR. Autosomal recessive.
