Genetics of CVD - Ting

Question 1

What is the main histological feature of HCM? Why do we see it?

Answer 1

Myofiber disarray

It’s caused by mutations in the sarcomere proteins

Question 2

Why is the presentation of HCM variable?

Answer 2

There are multiple possible sarcomere mutations; they can present very differently.

Question 3

What is the “classic” mutation in HCM?

Answer 3

MYH7

Question 4

How does HCM classically present?

Answer 4

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.

Question 5

How is HCM inherited?

Answer 5

Autosomal dominant inheritance, but can arise sporadically

Question 6

How is DCM inherited?

Answer 6

Mostly autosomal dominant inheritance, but can be X-linked, autosomal recessive, or mitochondrial

Question 7

What is the LMNA mutation?

Answer 7

An especially potent mutation that can lead to DCM

demonstrates pleiotrophy in that it also causes muscular dystrophy, neuropathy, arrhythmias, lipodystrophy, and progeria

Question 8

Who should be clinically screened for cardiomyopathy?

Answer 8

Asymptomatic first degree relatives

Relatives known to carry the mutation

Question 9

How often should clinical screening take place in patients with a KNOWN mutation?

Answer 9

Yearly during childhood, every 3 years after

EXCEPT ARVD, which is yearly after age 10 (it takes time for this mutation to present)

Question 10

How does familial hypercholesterolemia clincally present?

Answer 10

May present asymptomatic and be found with routine cholesterol screening (less common)
xanthomas

Question 11

How is familial hypercholesterolemia inherited? Why is this important?

Answer 11

Can be autosomal dominant or recessive

Recessive disease is homozygotic and presents earlier and more severely

Question 12

What mutations cause FH?

Answer 12

LDLR (60-80%)
APOB (1-5%)
PCSK9 (3-?%)

Question 13

Why is genetic testing required for FH?

Answer 13

Homozygotes will not respond to just one therapy; multiple, aggressive therapies are needed

Question 14

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

Answer 14

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

Question 15

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.

Answer 15

50%, 50%

Question 16

Describe the difference between REDUCED PENETRANCE and VARIABLE EXPRESSIVITY.

Answer 16

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

Question 17

Describe the difference between GENETIC HETEROGENEITY and PLEIOTROPY.

Answer 17

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)

Question 18

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?

Answer 18

1) Romano Ward Syndrome
2) Seizures
3) During exercise or high emotions

Question 19

Romano Ward Syndrome:

1) What is the inheritance pattern?
2) What are the three most commonly mutated genes?

Answer 19

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)

Question 20

What types of LQTS show increased risk of tachyarrhythmias (and SCD) during sleep?

Answer 20

LQTS2, LQTS3, LQTS6, & LQTS9.

Question 21

Name four ways LQTS can be treated / managed.

Answer 21

1) Beta-blockers
2) Pacemakers
3) Defibrillator access
4) Implantable cardioverter-defibrillators (ICDs)

Question 22

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?

Answer 22

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)?)

Question 23

What is the current genetic testing detection rate for LQTS? What does this mean?

Answer 23

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.)

Question 24

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?

Answer 24

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)

Question 25

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?

Answer 25

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

Question 26

CPVT:
Mutations in one of two genes result in the majority of cases. Name both genes, their functions, and their inheritance patterns.

Answer 26

1) RYR2.
Cardiac Ryanodine receptor channel.
Autosomal dominant.
2) CASQ2. 
Calsequestrin - a Ca2+ buffering protein of the SR.
Autosomal recessive.