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POM Test 2 > Pedigree > Flashcards

Pedigree Flashcards

1
Q

What pattern?

A

autosomal recessive

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2
Q

What is the risk of cancer?

  1. 75 y/o grandfather had colon cancer
  2. 65 y/o father had prostate cancer
  3. Cancer in multiple generations an young
A
  1. Low risk
  2. moderate risk
  3. high risk
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3
Q

Dominant phenotype

A

A phenotype that clinically manifests in the heterozyote. One copy of normal allele.

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4
Q

Incomplete or partial dominance

A

When phenotype manifests in a homozygote dominant.

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5
Q

Recessive phenotype

A

Phenotype that clinically manifests only in a homozygote (two copies of the mutation) or a compound heterozygote (two different mutations at the same locus).

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6
Q

Autosomal Dominant

What is it? What is chance children will have?

A

The presence of the allele is enough to cause the condition. There is a 50/50 chance children will have.

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7
Q

What type of pedigree is this?

Why?

A

Autosomal dominant

  • Why? Verticle transmission in multiple generations, male to male transmission, males and females equally likely to be affected, each affected individual has 50% chance of passing allele to each child
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8
Q

What are some examples of autosomal dominant conditions?

A

Neurofibromatosis types 1 and 2, huntington disease, BRCA1 mutation

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9
Q

Neurofibromatosis type 1

  • Are variants usually new mutations or does the person usually present with family history?
  • Does neurofibrosis pts need to have all the phenotype characteristics?
  • Should testing be done on children?
  • Pleiotropy
A
  • Variants are new mutations
  • Pts only need to have two of the phenotypes. Variable expression/expressivity.
  • Testing should be done because children won’t have the phenotype. Age related penetrance and 100% penetrant by adulthood.
  • Pleiotrophy is when one gene results in a lot of effects.
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10
Q

What is this an example of?

A

autosomal dominant with incomplete penetrance

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11
Q

What is this an example of?

A

Mosaicism

This is when some cells of the body are impacted and some are not. The first individual affected can be mosaic but the next individuals will not be mosaic.

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12
Q

“de novo” mutations

  • Are they inherited?
  • Are they passed on? Why not?
  • What are three examples?
A
  • They are not inherited they are mutatiosn that are associated with advanced paternal age and tend to accumulate with age in male gamete stem cells.
  • They are not passed on. Usually a syndrom that affects reproductive fitness (ability to have children) will not be passed on.
  • Examples are Marfan syndrome, Neurofibromatosis type I, and achondroplasia.
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13
Q

Autosomal Recessive

  • When is the phenotype expressed? (homozygotes or heterozygotes)
  • If the daughter is affected with the recessive condition what does this tell you about the parents?
  • Very rare disorders = increased chance of ______
  • unaccfected siblings have a ____ risk to be carrier
A
  • When the phenotype is expressed in homozygotes.
  • That both the parents are cariers.
  • very rare disorders increased chance of consanguinity
  • unaffected sibligns have a 2/3 risk to be a carrier
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14
Q

What does this pedigree show?

  • What type of transmission?
  • Are males and females equally affected?
  • What is a founder mutation?
A

Autosomal recessive pedigree

  • Horizontal transmission
  • Males and females equally
  • Founder mutations are mutations in the ancestial population that make certain conditions more common.
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15
Q

What are some examples of autosomal recessive conditions?

A

Sickle cell disease, cystic fibrosis, phenylketonuria (and most metabolism disorders)

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16
Q

X-linked inheritance

  • Where are the genes?
  • Do daughters generally get X linked chromosomes?
  • If a mother is a carrier what is the risk that a child will be affected?
  • What is the risk that a son will be affected?
  • What is the risk that daughter will be carrier?
A
  • The genes are on the X chromosome
  • Daughters do not because they have another X chromosome that is dominant and therefore their phenotype will be normal.
  • 25% risk that child will be affected
  • 50% risk that son will be affected.
  • 50% risk daughter will be carrier.
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17
Q

What pedigree is this?

  • What would you call the males? (hemizygotes or heterozygotes)
  • Even though the females are heterozygotes can they still express any phenotypes? Why?
A

X- linked

  • Would call the males hemizygotes (female sare heterozygotes)
  • Yes, females can still express phenotypes. Because of X-inactivation.
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18
Q

X-inactivation

  • What is it?
  • What is the inactive chromosome called?
A
  • One of the x chromosomes in each cell of female is inactivated. Not always 50-50
  • Barr body is inactive chromosome
  • Note: psydoautosomal region escapes inactivation
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19
Q

What type of pedigree is this?

  • What type of transmission? between who?
  • What do you notice about brothers and sisters
  • Can father transmit their recessive x-linked to their son? Why not?
  • Will daughters of affected males always be carriers? Why?
A

X- linked hemophelia

  • Vertical, mother to son
  • Affected brothers have carrier sisters.
  • No because fathers will always donate the Y chromosome to their sons. There is no male to male transmission.
  • Yes because fathers will donate their Xr chromosome to their daughter.
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20
Q

What are some examples of X- linked conditions?

A

Duchenne muscular dystrophy, hemophilia, rickets, incontinetia pigmenti

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21
Q

Mitochondrial Inheritance

  • The mitochondrial ____ is ______ inherited.
  • All of the embryo’s mitochondria are from the ______.
A
  • genome, maternally
  • mother
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22
Q

Homoplasmy

A

Variant that is present in all inherited mitochondria.

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23
Q

Heteroplasmy

A

Variant that is present in some fraction of the mitochondria. This causes clinical features to vary greatly (because there is a mixture of normal and abnormal mitochondria). The dosage of abonormal mitochondria will determine if a person is clinically impacted.

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24
Q

What is this pedigree an example of?

  • Can a man pass this mutation onto his offspring?
A

Mitochondrial inheritance

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25
Q

What are two examples of mitochondrial disorders?

A

Melas and Lebers

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26
Q

Codominance

A

When two alleles are codominant the expression of each allele can be detected even in the presence of the other. Example is blood type.

27
Q

Sum Rule

A

Probability that any one of a number of events will occur if they are mutually explusive. The sum of individual probabilities.

28
Q

Product Rule

A

Probability that multiple events will all occur. AND

29
Q
  • If a person has a recessive condition what is the probability that their parents are carriers?
  • 1st degree relatives (sibling and parents) have a ______ chance of also carrying the allele.
  • 2nd degree relatives (grandparents) have a _____ of carrying the allele.
  • Siblings of the person with the condition
A
  • 100%
  • 50%
  • 50%
  • 75%
30
Q

Silent mutation

A

same protein

31
Q

missense mutation

A

different protein

32
Q

nonsense mutation

A

stop codon

33
Q

frameshift deletion

A

change the entire frame

34
Q

Polymerase Chain Reaction

  • What are the three steps?
  • Why do you do this?
  • Is it fast/slow, expensive/inexpensive?
  • Can you detect mutations?
A
  • denaturation (heat), annealing (add primer), extension (Taq polymerase adds dNTP)
  • to amplify small amount of DNA
  • fast an inexpensive
  • can detect mutations
35
Q

Cystic fibrosis genetic testing

  • How do you do carrier testing in CF pts?
  • Do different populations ahve different pretest and post test risks?
  • What types of mutations does the screening panel detect?
  • Why only 23 mutations on the CFTR gene? Why not the whole gene?
A
  • Targeted PCR panel on the CFTR gene and include 23 common mutation (greater than .1% frequency)
  • Yes! common in Ashkenazi Jewish population and caucasians.
  • The screening panel of the 23 mutations on CFTR gene detects the mutations that are associated with classical CF.
  • Not whole gene because.. money, time, novel sequence variants, variants of unknown significance, not all mutations associated with classical CF, some only with milder symptoms
36
Q

DNA sequencing

  • What does it do?
  • What is the template?
  • What is incorporated?
  • What do you do after the ddNTP are incorporated?
A
  • Allows examination of the DNA nucleotide sequence up to 500 bases and it can detect single base changes as well as small insertions and deletions
  • PCR product is the template for sequencing
  • regular deoxynucleutides (with OH group that extends) AND ddNTP (with H) group that is florescently labeled and causes chain termination when incorporated.
  • Use gel electrophoresis to separate by size and have a computer analyze the florescent labels and compare with the reference sequence
37
Q

Molecular genetic testing of Hereditary Breast/Ovarian Cancer Syndrom

  • What is the mutation responsible?
  • How do you identify this mutation?
  • Which person would you test in the family? Why?
A
  • Mutation responsible is BRCA1 or BRCA2
  • identify by DNA sequencing
  • the person most likely to harbor the genetic variant (someone with the cancer). This is because if you know the cause in the family you can test for this particular variant.
38
Q
  • When do you use targeted analysis?
  • Is targeted analysis or gene sequencing faster/less expensive?
  • Clear cut interpretation?
A
  • When mutations are known, there are few mutations.
  • Targeted
  • yes
39
Q
  • When do you use gene sequencing?
    *
A
  • Use gene sequencing when mutations are unknown and targeted analysis is negative. Mutations will occur throughout the gene.
40
Q
  • What do you use for single nucleotide variants and small insertions and deletions?
  • What do you use for larger indels and whole or partial gene deletions/duplications?
  • What do you use for genomic rearrangements?
A
  • PCR based and DNA sequencing
  • Deletion/duplication analysis
  • Cytogenetic karyotyping, FISH
41
Q
  • What is an example of large scale genomic analysis
  • What is the advantage?
  • Can you sequence the exons? genome?
A
  • NextGen Sequencing
  • Genetic panels for specific conditions with multiple genes involved (ex developmental delay, hearing loss, hereditary cancer syndromes, somatic mutations in turmors
  • Can sequence the “whole exome sequencing (WES)” and the “whole genome sequencing (WGS)”
42
Q

NextGen Sequencing

  • How does it happen?
  • What are the advantages?
  • What are the disadvantages?
A
  • micro/nanotechnology to sequence millions of reactions
  • advantages are that it yields massive amounts of information
  • disadvantages are that it requires and expertise to analyze data and it is not good for detection of genomic structural rearragements/repeat regions
43
Q

Variant of Uncertain Significance

A

Genetic variants that we do not know what they mean and might have little or no clinical effect.

44
Q

Describe the test results you get from these different genetic tests

  1. targeted mutation analysis
  2. gene sequencing
  3. whole exome sequencing
  4. whole genome sequencing
A
  1. specific limited information that is easier to interpret
  2. more difficult to interpret
  3. too much information possibly/increased potential for over interpretation and variants of uncertain significance come in
  4. too much information possibly/increased potential for over interpretation and variants of uncertain significance come in
45
Q

Linkage

A

genes that are close enough on the chromosome that they are inherited together

46
Q

Linkage disequilibrum

A

non-random association of alleles (two traits being inherited together)

47
Q

Chromosome abnormality

A

Mutations that change either the number or structure of chromosomes (ex of strucutre is insertion, deletion, ring, inversion, translocation - reciprocal or robertsonium)

48
Q

Karyotyping (G-banding)

  • What are some of the advantages?
  • What are some of the disadvantages?
A
  • advanages
    • evaluation entire genome
    • used to detect gains and loses of entire chromosomes
  • disadvantages
    • need viable cells (in metaphase)
    • resolution limited to 3-5 Mb or greater
    • only for fairly large chromosomal regions
49
Q
  • What happens after a duplication, deletion, gene interuption?
  • Gene fusion, what can that do?
A
  • An Increase and/or decrease in gene products.
  • Can alter the protein - create one with an altered function. The regulatory region of one gene could have been moved in front of another.
50
Q

What are some phenotypes of chromosome abonormalities?

A
  • Cancer
  • Abnormal growth and development in children and pregnancies
    • intellectual disabilities
    • birth defects
    • dysmorphic features
  • death
  • clinically abnormal offspring, miscarriages and or infertility
51
Q

Robertsonian translocation

A

When you have two small chromosomes combined to each other. People who have this might have the right number off chromosomes but have likely hood that they will have messed up chromosome passing to children.

52
Q

FISH (fluroescence in situ hybridization)

  • What are the positives?
  • What are the negatives?
  • What situations can FISH help with?
A
  • Positives
    • high resolution
    • interphase can be performed on noviable cells
  • negatives
    • requires a clinically directed search that is VERY specific
  • fish can help with microdeletion and microduplication syndroms
53
Q

Microdeletion and Microduplication

A

syndroms that are characterized by small recurring interstitial deletions or duplications that are associated with a described phenotype

54
Q

DiGeorge Microdeletion Syndrome

  • Symptoms?
  • Explain the image.
A
  • symptoms: specific facial features, palate, heart abornmal, learning disabilities, hypocalcemia, immune deficiency, psychiatric
  • Image: DiGeorge Syndrome can be identified with FISH. You can see the red TPLE1/HIRA on chrom 22 region that was where the prob hydrolized to. That is what is usually deleted. Underneath you can see where the control is replicated twice but the critical region is not.
  • Can see in both metaphase and interphase FISH.
55
Q

Microwarray Technology

  • What are the positives
  • What are the negatives
A
  • positives:
    • can survey the entire genome
    • high resolution
    • can use nonviable cells
    • allow us to identify consanguinity and uniparental disomy
    • first tier test
      • will detect most of cytogenetic abnormalities
      • detect small chromosomal disorders
  • negatives
    • does not provide information about mechanism responsible for gain and loss (cannot identify translocation)
    • have increased Variants of Unclear Clinical Significance
56
Q

Explain this picture

A
  • Isolate DNA and lable it with green florescent
  • Allow it to hybridize to a chip that has arrayed DNA
  • Each circle has a different locus of a genome that we are interested in
  • If you have a duplication you will have intense hybridization, if you have a deletion you will have a weak hybridization signal and if it is normal you will have moderate hybridization.
57
Q

Explain this picture

A

This is data from microarray technology, specifically an Affymetrix CytoScan HD. The hybridization signal at each locus is compared to data from controls and plotted as log 2 ratio of 0. Negative values means weak hybridization (missing) and + values mean intesnse hybridization (gain).

58
Q

Why is FISH metaphase better than FISH interphase?

A

because you can see where the chromsome goes (identify the translocation if there is one)

59
Q

Uniparental Disomy

A

The inheritance of both copies of an allele from one parent and none from the other parent.

60
Q

SNP

A

single nucleotide polymorphism

this is variation at a single site within a DNA sequence. for each pair of chromosomes there are two possible SNP alleles at each locus AT or GC.

61
Q

What do SNP Microarrays show?

A

SNP Microarrays show uniparental disomy and consanguinity.

62
Q
  • What does this show?
  • What is the phenotype?
  • Increased risk of…
A
  • comlete unipararental isodisomy 6
  • two copies of chromosome 6 from same parent because the array is telling us that we have complete homozygosity. Homozygot for each SNP marker on the chromosome.
  • Phenotype is transient neonatal diabeties and imprinting effect
  • increased risk of recessive disease and mosaicism for anueploidy
63
Q

What does this show?

A

consanguinity

regions of homozygosity scattered throughout

64
Q
A

POM Test 2 (8 decks)

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