Lecture 17

Question 1

Why compared to many other areas of medicine does medical genetics need to have a strong
emphasis on the patient’s family in addition to the patient?

Answer 1

the family has a critical role in the care of the patient

the family also needs to be assessed to assure future children of immediate family are not at risk

Question 2

Design an assay that would allow for the disease allele of the huntingtin gene to be identified using
PCR.

Answer 2

If you amplify the Huntington gene with PCR and run gel electrophoresis you would be able to separate the amplified genes by molecular weight. Those that are higher up on the gel are larger and have a lot of trinucleotide repeats and are thus the diseased gene.

Question 3

Why does presymptomatic testing of Huntington’s disease entail complex ethical issues?

Answer 3

Getting presymptomatic testing could have implications for individuals other than you that may not want to know such as your father or sibling

Question 4

What is maternal serum sampling? Is it a diagnostic test? Why nor why not?

Answer 4

Maternal serum sampling is the extraction of amniotic fluid by injecting a needle into the amniotic sac.

it is not a diagnostic test as there are false negatives and positives and is not 100% accurate

Question 5

Why is fetal cell sorting in principle easier for male fetuses? Describe two reasons why fetal cell
sorting is very difficult.

Answer 5

In an xx mother who is pregnant you would expect only xx chromosomes so when a Y chromosome is encounter in the fetal cell collection you know it would be from the male fetus

Question 6

What are amniocentesis and chorionic villus sampling? Would these procedures typically be
recommended before an abnormal result from a noninvasive test? Why or why not?

Answer 6

amniocentesis is where a needle punctures the uterus to extract amniotic fluid and culture the fetal cells and genotype said cells for diseased genes
1/400 risk for miscarriage

chorionic villus sampling: more risky than amniocentesis
a tube is passed transvaginally to take cells off of the chorion and culture said cells for genotyping
1/200 risk of miscarriage

these are only recommended after a noninvasive test gives an abnormal result as they are more accurate but carry far more risk

Question 7

Describe the process of preimplantation screening and how it can be used to mitigate the risk of a
child with a genetic disease. In what context is this method typically used?

Answer 7

induce ovulation using hormones in females

the egs are frozen or fertilized in the lab

the embryos go through several rounds of cell division. You take one cell from the embryo genotype it for a disease and exclude said embryo from insertion into the uterus. has a 50% success rate

Question 8

What is the Guthrie test? How does it work?

Answer 8

you take a blood sample using a heel stick of the newborn as it is the least pain-inducing and you test the blood.

To test the blood for PKU, you plate bacterium from the blood on a plate with a toxic phenylalanine analog. If the individual has high levels of PKU in their blood it will restore bacteria growth on the plate.

Question 9

Why are population carrier screens performed for Tay-Sachs disease? What is the molecular basis
of pathogenesis in Tay-Sachs disease?

Answer 9

It is done at a population level because the Ashkenazi Jewish populations have high rates of this disease.

Tay Sachs disease is due to a lack of a function hexosimidase protein which leads to a buildup of GM2 ganglioside which kills nerves.

Question 10

Are direct-to-consumer genetic tests diagnostic? Why or why not?

Question 11

Describe one potential drawback of direct-to-consumer genetic testing in the absence of the
support of a genetic counselor

Answer 11

without a genetic counselor people who receive for example an alph-1 antitrysin mutation likely wouldn’t know that other things such as smoking would exacerbate their likely hood getting COPD.

individuals would not know how to interpret the results

Question 12

Given the following pedigree concerning an autosomal recessive condition with a carrier
frequency of 3.2%, calculate the probability that individual III-1 will be affected by the disease. How
does this compare to the rate of disease expected for a random mating? Formulate a 2-3 sentence
explanation of these odds as if you were a genetic counselor and II-1 and II-2 were in your office
seeking guidance.

Answer 12

1/4: chance of being autosomal recessive

Individual II-2: has 2/3 of being a carrier

II-1: don’t know the genotype so you use a normal carrier frequency of 3.2%

Question 13

How is cancer a “disease of the genome”?

Answer 13

it is a catch all term for 200 different diseases affecting different organs, tissues, and cell types

Question 14

Cancer can be thought of as natural selection playing out among somatic cells. Explain this idea.

Answer 14

cells with mutations evade apoptosis and are therefore more fit to prolferate amidst regulatory mechanism in place to remove tumors.

Question 15

Define proto-oncogene, tumor suppressor gene, angiogenesis, metastasis, driver mutation, and
passenger mutation.

Answer 15

proto-oncogene: are genes that typically drive the cell cycle forward..

a gain of function mutation to a proto-oncogene turns it into a oncogene will lead to over dividing of cells seen as “gas pedal”

tumor suppressor gene: slow the cell cycle due to environmental cues
however LOF mutation in TSG leads to their being no “brake mechanism” against the “gas pedal”

angiogenesis induction: accumulation of blood vessels in tumors as they grow

metastasis: tumors that spread to other parts of the body

Driver mutation: give rise to cancerous pehnotype

passenger mutation: are present in the tumor but arrent causing the phenotype

Question 16

Why is age the biggest risk factor for cancer?

Answer 16

As you age you undergo more and more cell divisions there is a gradual accumulation of mutations

Question 17

Contrast sporadic and familial cancers. How do they differ?

Answer 17

sporadic: gradual accumulation mutations that transition normal cells to cancerous ones as we age

everyone is equal risk to sporatic cancer
account fr 90% of all cancers

familial cancer: predisposition to a cancer due to mutation in the germline which makes some people more likely to have it than others

Question 18

Explain the cause of chronic myelogenous leukemia. How can it be treated by Gleevec?

Answer 18

its a cancer of the blood due to over production of the white blood cells

translocation of between chromosome 9 and 22

on the translocated short Philadelphia chromosome c-able and BCR to be close to each other on the chromosome–> RESULTS IN BCR BEING CONSTIUTIVVELY EXPRESSED as it is under the regulatory control of

Gleevec inhibits the fusion protein and stops the over production of granulocytes( the result of BCR being constitutively expressed)

Question 19

Explain Knudson’s two hit hypothesis using the example of retinoblastoma.

Answer 19

If recessive mutation causing cancers are already having at a low rate per cell driving those who are heterozygous will be at a much higher risk

sporadic retinoblastoma: is rare as you need two alleles to have mutations and will typically only affect one eye

for familial retinoblastoma: you are already predisposed as you are heterozygous and therefore only one hit of the mutation will cause the cancer so it is more common

RB1 encodes pRB that usually binds etuF which sends signals for growth… BUT if RB1 is mutates pRB is mutated and cant etuF so etuF is contsituivelyb expressed leasding to constant growth signals and over growth cells

Question 20

Li Fraumeni syndrome can lead to inheritance of susceptibility to many types of cancer. What
explains this?

Answer 20

mutation in tp53 whic h encoded is ththe p53 tumor repressor gene that prevents entering the s phase of cell cycle due to DNA damaging.

those with Li Fraumeni syndrome are heterozygous for a mutation to the p53 gene in their cell lineage. So like hereditary cancers they need one hit of the mutation to have a dysfunctional p53 gene.

Without p53 cells with damage proliferate and give rise to more mutations.

Question 21

Most cases of breast cancer are sporadic. What can indicate that a case is due to inherited
susceptibility rather than being sporadic?

Answer 21

Indications:
predisposition typically Bilateral cancer: only affecting one breast or ovary

contralateral: following cancer in one breast you get cancer in the other at a later date

breast cancer at an earlier age ( before 40) can indicate the predisposition to it

LOF mutations in the BRCA 1 and BRCA 2 genes increase the susceptibility to breast cancer as individuals who are heterozygous for the mutation would only need one hit of a mutation to get breast cancer.

not everyone who has a mutation in BRCA 1 and 2 will develop breast cancer,

Question 22

Why do mutations in BRCA1 and 2 lead to increased risk of cancer? Is this similar to why TP53
mutations lead to an increased risk of cancer? Explain.

Answer 22

BRCA 1 and 2 control dna damage repair.

yes, this is due to there only needing to be one hit of the mutation to cause the cancer. For these individuals with hereditary mutation, the genes only need another mutation to develop cancer therefore they have increased susceptibility to it.

Question 23

Why are certain cancers not treatable by surgery? Why do chemotherapeutics typically target
rapidly dividing cells?

Answer 23

chemotherapy: drugs injected to kill rapidly dividing cells

radiation: take ionized radiation and aim it at the tumor

cancer gneomics: sequencing cancer genomics to determine types of mutations that lead to disease

surgery is not always effective because by removing tumor from tissue you could be removing healthy tissue in things such as brain cancer which could lead to neurological

chemotherapeutic typically target rapidly dividing cells as cancerous cells are rapidly dividing

Question 24

Explain the logic of CAR-T cell therapy to treat ALL. Explain the dual consequences of on-target
off tumor cytotoxicity of these cells against CD-19 positive B-cells.

Answer 24

isolate T-cells from patients, you modify their anitgen receptor to bind CD-19 expressed by cancer cells, you grow these cells up, and inject them into the patient.

As a result, you would expect these CAR-T cells to detect cancerous cells where the antibody of CD-19 would bind the antigen and destroy the cancerous cells.

There are dual consequences:
there are noncancerous CD-19-expressing cells that can bind to CAR-T and be destroyed.

B-cells produce antibodies to fight infection and because they are CD-19 positive they can be destroyed resulting in B-cell aplasia and compromised immune function.