long QT syndrome

clattergumneckBiotechnology

Oct 23, 2013 (4 years and 17 days ago)

1,887 views

Roger Maxwell is very health
-
conscious. He runs, swims, and hikes; follows a low
-
carbohydrate
diet; and generally feels great. He sees a physician when he needs to, in addition to annual
physical exams at the large company where he is an engineer. He'd
never allow himself to get so
out of shape that heart disease would be a risk. Because of his strict adherence to this healthy
lifestyle, Roger is surprised when a medical intern, gazing at his yearly electrocardiogram (ECG)
at his work physical, clearly p
icks up on something.

“What? What are you looking at?” Roger blurts out while buttoning up his shirt.

“Oh, it's probably nothing.” But she doesn't look like it's probably nothing.

“The heart murmur? My mom's been telling me about it since childhood. Not a
big deal. The
doctors called it something last year, something I never heard of.”

“Did you check it out?” asks the intern.

“Nah. It wasn't bothering me, so I forgot about it. Why? What's wrong?”

“Well, maybe you should ask the doctor to explain it again an
d suggest what to do.”

“About what?”

“The doctor will explain it. Please don't worry, though,” says the intern as she rushes off to the
next patient.

Roger's electrocardiograms had in fact been showing that he has had long QT syndrome, and not
a heart murm
ur, for many years. The doctor explains that this is a problem with the heart's
rhythm, and not its valves. Roger goes home and Googles
long QT syndrome

right away. What
he finds concerns him enough to alert his relatives.

Long QT syndrome is a lengthening in the time that it takes the ventricles (the lower two heart
chambers) to recover after a contraction, called the QT interval on an electrocardiogram. This
delay is called
torsade de pointes,

and it causes lightheadedness

upon standing or even fainting,
as blood pressure drops when the heart rhythm becomes abnormal. If the arrhythmia turns into
the more erratic condition called ventricular fibrillation, it can be deadly. Some cases of sudden
cardiac arrest in people who ap
parently do not have heart disease are in fact due to long QT
syndrome. This may have been the case with Roger's aunt, Amelia, his mother's sister, who died
at age 34 of what was thought to be a heart attack, but, now Roger realizes, was more likely an
arr
hythmia. Still, with only one affected relative, Roger had never thought of his aunt's early
demise as a family history, especially since his mother is healthy.

Roger reads that in people with some forms of long QT syndrome, fatal arrhythmia can be
trigger
ed by intense emotions or a sudden loud sound. The first recorded case of the condition
was a little girl, who collapsed dead when her teacher suddenly yelled at her. Her older brother
had died in a similar circumstance. Suddenly, Roger remembers that his
daughter Sheila faints
very easily. She even passed out once at a rock concert because she got so excited. He'd never
panicked over it because his mother fainted easily, too. A pattern was emerging.

Long QT syndrome is caused by mutations in any of at leas
t 10 genes that encode either proteins
that form parts of ion channels (potassium, sodium, or calcium) or proteins that affect the
functioning of these channels. Ion channels control the spread of nerve impulses and the
resulting muscle contraction. The ti
me for the heart's recovery after a beat, called
repolarization,

extends the period when ions are trapped inside heart muscle cells because the channels are
blocked, too slow to open, or too quick to close in people who are at elevated risk due to
inheriti
ng a mutation. People with long QT syndrome can experience arrhythmia if they take
certain drugs that prolong the QT interval. These drugs include certain antibiotics,
antidepressants, and diuretics (“water pills”).

Roger reads about the different genes an
d drug combinations that cause long QT syndrome on
Wikipedia, and then he scans
www.genetests.org

to find labs that test for all of them. Only then
does he make an appointment with a cardiologist, and he arranges to

have his blood and that of
his daughter and mother sent to one of the labs. Two weeks later, he learns that they all have a
dominant mutation in a gene called
HERG

(for “human ether
-
a
-
go
-
go”) that causes long QT
syndrome type 2 (LQT2). Even healthy family

members could have inherited the mutation,
because 15 percent of people with long QT syndrome do not have symptoms. The concern is
their increased risk of developing symptoms in the future

perhaps suddenly.



1. Roger is upset that in the past doctors had n
ot been more insistent that he follow up on
the abnormal ECG pattern. When he mentions this to his primary care physician, she
answers, “I didn't say anything because you are so healthy, and people who have cardiac
arrest from long QT do so in young adulth
ood. You're too old to worry about it.” But
Roger should be worried, because

o

a. he looks younger than he is, so could still be at risk.

o

b. the condition can be inherited, so others in the family could be affected.

o

c. he could die at any time.

o

d. he can

no longer take antibiotics.

o

e. long QT syndrome can cause cholesterol to build up in his coronary arteries.



2. Individuals who should take genetic tests for long QT syndrome are

o

a. all the people in generation IV.

o

b. Eric, Joan and Peter, and then Dyl
an, Anika, Sean, Keri, and Anna if a parent
has the mutation.

o

c. Juanita, Larry, Joan, Peter, and Ellie.

o

d. Abe, Sara, Craig, Philip, Edwin, and Yvonne.

o

e. Only those who are athletic.



3. The mode of inheritance of long QT syndrome in the Maxwell family is

o

a. X
-
linked recessive.

o

b. autosomal recessive.

o

c. autosomal dominant.

o

d. sex
-
limited.

o

e. X
-
linked dominant.



4. Some people who inherit the same mutation as Roger do not experienc
e any
symptoms. This means that the mutation is

o

a. variably expressive.

o

b. genetically heterogeneic.

o

c. polygenic.

o

d. incompletely penetrant.

o

e. dominant.



5. The fact that mutations in any of several genes can cause long QT syndrome means
that the co
ndition is

o

a. variably expressive.

o

b. genetically heterogeneic.

o

c. polygenic.

o

d. incompletely penetrant.

o

e. recessive.



6. The risk that Sean, Keri, or Anna has inherited the family's mutation for long QT
syndrome is___.

o

a. 1

o

b.

o

c. ½

o

d. ¼

o

e.



7. Roger is relieved that he does not have LQT7, which affects skeletal as well as cardiac
muscle, causing short stature and scoliosis. He is also glad that he doesn't have LQT8,
which causes many symptoms, or either of two types that also cause deafness.
These
other forms of the condition, with more than one symptom, exhibit

o

a. invariable expressivity.

o

b. complete penetrance.

o

c. genetic homogeneity.

o

d. pleiotropy.

o

e. phenocopy.



8. The reason that mutations in different genes all cause the same phenot
ype of extended
QT interval on an ECG is that

o

a. the heart is an extremely complex organ.

o

b. the genes all encode proteins that affect ion channels essential for maintaining
heartbeat.

o

c. the genes all encode the same protein.

o

d. the mutations all affe
ct the genes in the same way.

o

e. the QT interval is highly variable, even within individuals at different times.



9. A phenotypic pattern in a family that could be due to inherited long QT syndrome is

o

a. sudden cardiac death in one or more young people a
nd individuals who faint
easily.

o

b. many individuals who eat a very fatty diet and are sedentary but do not develop
heart disease.

o

c. many individuals with hypertension.

o

d. many individuals who suffer heart attacks after age 50.

o

e. a family with many a
thletes who have very low heart rates because of intense
and frequent exercise.



10. Discuss how incomplete penetrance, variable expressivity, pleiotropy, and genetic
heterogeneity can affect the severity of a disease in a family.



11. A person can lower risk of preventable types of cardiovascular disease by exercising
regularly and following a diet low in saturated fats and simple carbohydrates and high in
fruits and vegetables. Why are these approaches ineffective against long QT s
yndrome?



12. Explain how the molecular bases of the various forms of long QT syndrome make
genetic heterogeneity very likely.

Synesthesia Revisited

Peter Maxwell is lucky. In addition to his beautiful red shiny hair and musical gifts, he has
escaped the
family's long QT syndrome and is a synesthete. However, he isn't entirely convinced
that he has his genes to thank that musical notes appear colored to him. Instead, he worries that it
was his experimentation with LSD in the 1960s and its persistent effect
s that have caused what
appears to be synesthesia

he can't remember when he first noticed it.



13. The association of LSD use with synesthesia is an example of

o

a. a phenotype.

o

b. a genotype.

o

c. a pleiotropy.

o

d. a phenocopy.

o

e. incomplete penetrance.



1
4. The fact that Peter and Sean connect musical notes to color, but Anna sees letters,
numbers, and words as colors indicates that synesthesia is

o

a. not inherited.

o

b. variably expressive.

o

c. contagious.

o

d. incompletely penetrant.

o

e. a learned behavior
.



15. The genome
-
wide association study that identified genome regions where DNA
sequence variants are more common among people with synesthesia tracked the number
of specific short DNA sequences, called
short tandem repeats

(STRs). This approach of
assoc
iating part of the genome sequence with a trait is based on the concept of

o

a. Mendelian inheritance.

o

b. mutation.

o

c. pedigree construction and analysis.

o

d. genetic linkage.

o

e. biotechnology.



16. After Peter learns about synesthesia

from his son, he quizzes his parents to see if they
have the condition, too. Abe is a retired engineer, and his mother did not have a career.
Neither was particularly talented, in music or art. However, Sarah's mother, Linda, was a
landscape painter. Sara
h recalled that she'd sometimes say weird things, such as a
particular food tasted like a specific color. A possible inheritance pattern that might
explain this family history is

o

a. autosomal dominant with incomplete penetrance.

o

b. autosomal recessive wi
th complete penetrance.

o

c. several new mutations.

o

d. X
-
linked inheritance.

o

e. none of the above.



17. In some families, synesthesia is traced to a mutation in the
TBR1

gene, and in other
families to any of three other different genes. Therefore, synesth
esia is

o

a. pleiotropic.

o

b. genetically heterogeneic.

o

c. incompletely penetrant.

o

d. variably expressive.

o

e. not inherited.



18. Sean's predicament of one inherited characteristic

tune deafness

altering the
expression of another

rock star voice

is an ex
ample of

o

a. dominance.

o

b. recessiveness.

o

c. epigenetics.

o

d. epistasis.

o

e. a phenocopy.



19. List the evidence that Peter's synesthesia is not the result of his LSD use.



20. Discuss how genome
-
wide association studies and brain imaging have contributed to
our understanding of synesthesia.



21. Suggest an experiment that can distinguish whether synesthesia is inherited or a
learned behavior.