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MCBG TEST 2!!! > 8-22 Clinical Cytogenetics > Flashcards

8-22 Clinical Cytogenetics Flashcards

0
Q

What are the 6 Clinical Indications for Cytogenetic Analysis

A

“K I S M E C before you can do cytogenetic analysis of ur strnge chromosome”

  1. Early childhood physical or mental development abnormalities (failure to thrive,strange physical/internal orgn appearance, ambigous genitalia, retardation, Down syndrome)
  2. Stillbirth/neonatal deaths that appear to have cytogenetic abnormality
  3. Infertility or recurrent miscarriage hx in women
  4. Known or suspected chromosomal abnormality in a FIRST RELATIVE(parent or sibling)
  5. Mothers older than 35
  6. Cancer [chromosomal analysis of cancerous tissue]
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1
Q

What is Clinical Cytogenetics?

A

The study of chromosomal number and structure abnormalities and how that relates to human disease

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2
Q

Cytogenetic abnormalities (_____ abnormalities) are ___[more/less] common than other Mendelian single gene disorders. They are found in~ ____(#) live births

A

Cytogenetic abnormalities (CHROMOSOME # and structure problms) are MORE COMMON than any other Mendelian single gene disorder. Found in ~1/154 live births. [worst for mothers over 35]

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3
Q

What are the 6 types of dividing nucleated cells or tissues that are actually used to carry out cytogenetic analysis?
(also list the associated techniques to obtain them)

A

“We use FAWCC-B tissue cells to carry out cytogenetic analysis”

  1. Fibroblast (skin biopsy)
  2. Amniotic cells (via amniocentesis)
  3. White blood cells (T-lymph) from peripheral blood
  4. Chorionic Villi cells(xtra embryonic fetal tissue that forms surface of chorionic sac–>Chorionic Villus Sampling, CVS)
  5. Cancer Cells (tumor biopsy)
  6. Bone marrow cells (bone marrow biopsy for hematological malignancies)
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4
Q

1) How are human Chromosomes identified and distinguished from other Chromosomes?
2) Which technique is utilized to actually do this? [2]

A

1)Human chromosomes are identified based on the position of their centromere (3 diff positions) visualized by selectively
trypsin-staining unique chromosome band patterns
[Metacentric=centromere is midway
**SubMetacentric=off-center->chromosomal arms of unequal length
**acrocentric=centromere VERY NEAR 1 specific end–>petite chromosomal satellite arm ]

2)precise unambiguous trypsin-staining of unique chromosome band patterns (AKA G-banding) are done by ISCN{International System for Human Cytogenetic Nomenclature}
=Has to be at least 400 bands/karytype which is LOW resolution :-(

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5
Q

How does the ISCN chromosome band numbering system work??

2)What does a band numbered: 2p12 mean?

A

1) Numbering of regions<p> begins @ centromere (found in between arms) and moves outward (# INC) toward telomere ends.
* *Each arm has its own numbering system!

2) [2p12]=2nd Chromosome/P-arm/1st region/2nd band within 1st region

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6
Q

1) What are some advantages of the chromosome band numbering system when describing cytogenetic abnormalities
2) How do we obtain HIGH RESOLUTION chromosome band stains?

A

1) Cytogenetic abnormalities can be located and isolated more easily if able to be visualized and numerically tagged for location.
2) HIGH RESOLUTION band staining (550-850 bands/karyotype) are best obtained when chromosomes are in {PROMETAPHASE or PROPHASE}>less condensed vs. metaphase[low resoltn]

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7
Q

Describe Dark Bands (AKA ___ Bands) produced during

centromere-determining chromosome band staining [5]

A
  • *Dark Bands correspond with G Bands!**
  • AT-rich
  • Stains strongly w/Quinicrine
  • Gene Poor
  • [Alu] poor but [LINE-Long interspersed nuclear elements] rich
  • Condenses early in cell cycle but Replicates Late
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8
Q

Aneuploidy is usually a result of ___ ____. Partial aneuploidies arise from ____ or _____ of chromosome segments. Aneuploidy is defined as…..

A

Aneuploidy is typically result of MEIOTIC NONDISJUNCTION.

Partial aneuploidies arise from INSERTIONS/duplications or DELETIONS of chromosome segments.

Aneuploidy=most common type of human chromosome disorder in which there is an abnormality of chromosome #

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9
Q

Describe pale/light Bands or (AKA ___ Bands) produced during
centromere-determining chromosome band staining [7]

A

pale/light bands of [G] = R bands/R-banding
So..if you get Dark bands with R-banding or light bands with [Giemsa]=

  • GC rich
  • ALU/sine -RICH // LINE Poor
  • Gene RICH
  • stains weakly w/Quinicrine :-(
  • REVERSE of what’s made by Giemsa
  • standard for ALL EUROPEAN and some US labs
  • Condenses LATE during cell cycle and REPLICATES EARLY
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10
Q

1) What is Non-Disjunction?
2) What happens if ND occurs during MEIOSIS 1?
3) what happens if ND occurs in Meiosis 2?

A

1) Meiosis error where chromosomes fail to detach from each other during 1 of the 2 meiotic stages.
2) ND in MEIOSIS 1=makes 1st gamete#1 with BOTH HOMOLOG COPIES[1 mom AND 1 Dad homolog] in 1 cell and the other gamete #2 with nothing :-(
- ————— ———————— ———————— ———
3) ND occuring in Meiosis 2=1 out of the 4 gametes having 2 SISTER CHROMATIDS still attached to each other vs. 1(normal) in each of the 4 gamete cells

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11
Q

Insertion

A

An Unbalanced transfer of a segment from Chromosome #1 to Chromosome #2

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12
Q

Monosomy (____) and are most of the time ______

A

Monosomy (only having 1 X–>Turnr Syndrome,females) are MOST OF THE TIME LETHAL

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13
Q

What genotype is found in Klinefelter syndrome?

A

(47,XXY and 48,XXXY)

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14
Q

Chromosomal Unbalanced rearrangement

A

partial chromosome duplication–>partial trisomy
partial chromosome deletion–>partial monosomy
*Unbalanced rearrangmnt likely to produce abnormal phenotype

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15
Q

A.-Duplications and deletions are likely to occur from what? [2]

B.-Which is more serious phenotype?

A

Duplications & Deletions[MORE SERIOUS PHENOTYPE] can come from
1) unequal cross over between misaligned sister chromatids OR

2) homologous chromosomes with long repeated areas of super similar DNA sequences

16
Q

1) How are Ring Chromosomes formed?

2) What does the “ring” structure ultimately mean for that chromosome?

A

1) Double Stranded breaks in each arm of the parent chromosome form unstable Ring Chromosomes during mitosis

2)Ring Chromos either LACK centromere [ACENTRIC] or has 2 centromeres [Dicentric]—>2 things:
A-unable to form kinetochore and attach to mitotic spindle
B-will likely be destroyed when the 2 centromeres are simulatenously pulled to opposite poles of a dividing cell

17
Q

What is an Isochromosome?

2)What dz is often associated w/ this abnormality?

A

A chromosome which has lost one of its arms and so it replaces that 1st lost arm with an exact copy of the 2nd arm that wasn’t lost!! :-O =2 identical 2nd arms

2)15% of TURNER SYNDROME have this genotype

18
Q

1) InVERsion?
2) What are the two types of InVERsion?
3) What’s likely phenotype for InVERsions?

A

1)InVERsion=happens when a chromosomes breaks in 2 places and the segment between the breaks…inverts

2)PARACENTRIC inveRsion=breaks occur on the SAME chromosome arm
Pericentric=breaks happen on opposite arms and encompasses centromere.

3)InVERsion phenotype=likely normal looking since both inversions produce balanced chromosome

19
Q
  • Balanced Rearrangement

* What’s an example?

A

A likely “conservative” (no phenotypic affect) type of change in which all chromosomal material is still present but just in a different order.

Ex. Inversions

20
Q

Although Inversions are typically considered “balanced” (No Phenotype effect) –>Meiosis I Crossover in gametes between normal and INVERTED chromosomes would produce what type of outcomes…….

A

Meiosis I crossover between normal & inverted chromosomes in the gametes will produce different outcomes for ALL gametes formed [possibly bad]

21
Q

WWhat is the difference between chromosomes who are

STABLE VS. UNSTABLE during rearrangements?

A

STABLE VS. UNSTABLE depends on whether or not the altered chromosome retains certain features of a normal chromosome.

22
Q

What are Reciprocal Translocations? [2]

A

Balanced Translocation in which chromosomal material is reciprocally exchanged between 2 different homologs.

-Is usually Ok for host but BAD FOR HOST GAMETES/PROGENY since there is possible 3:1 segregation/Non-disjunction that can occur in which gamete receives UNBALANCED EVERYTHING

23
Q

1) What is Robertsonian Translocation?
2) In which chromosomes does it occur in?

3)Why does the loss of the p-arms in Robertsonian translocation NOT cause an abnormal phenotype?

A

1) crossover event involving long stretches of repeated DNA sequences (rDNA=encodes for rRNA) inside the short arms [p-arms] of acrocentric chromosomes. These rDNA within the short arms “trade places” because both centromeres are present but are so close togethr they function as one :-/.
2. Occurs only on the 5 acrocentric chromosomes [13,14,15,21 & 22]
3. the resulting acrocentric fragment of the 2 short arm pieces joining together is lost but causes no harm to the host because that same repeated rDNA sequence can be found elsewhere in other unaffected acrocentric chromosomes

24
Q

1) Which mode of Reciprocal Translocations typically result in unbalanced abnormal progeny? [2]
2) Which modes result in typically normal offspring?

A

1)Adjacent segregation (2:2) and
ANY 3:1 SEGREGATION = UNBALANCED OFFSPRING :-(

2)Alternate segregation(2:2) whether normal or balanced still gives normal progeny

25
Q

1) What is MICRODELETIONS/DUPLICATIONS syndrome? [2]
2) How are MICRODELETIONS/DUPLICATIONS formed?

3) How is this related to “Contiguous Gene Syndrome”
4) What type of technique can be used to detect these abnormality?

A

1) small DNA deletions often affecting a group of neighboring genes–and difficult to detect w/classic cytogenetic techniques
2) formed by UNEQUAL CROSSING between either *A-Misaligned Sister Chromatids or **B-homologous chromosomes that have super similar DNA seq. repeats between them–>deletion or duplication
3) Microdeletion/Duplications are also called Contiguous Gene Syndrome because they usually affect neighboring genes AND sx severity depends on # of genes affectd
4) FISH[Fluorescence In situ Hybridization] can detect these small microdeletions/duplications not able to be detected w/chromosome banding/cytogenetics

26
Q

What are the common genetic diseases associated w/DNA MICRODELETIONS/DUPLICATIONS? [6]
*PNC DHC-W

A

1.DiGeorge syndrome=most cmmon cytogenetic deletion->cause of 5% congenital heart defects in newborns

  1. Prader-Willi/Angelman=
  2. Neurofibromatosis=
  3. Charcot-Marie-Tooth=
  4. Williams syndme=
  5. Cat eye syndrome =
  6. HNLPP=
27
Q

What is Spectral Karyotyping?

A

Type of FISH that creates a “chromosome painting” full of specific fluorophore probes–>allows us to see multicolor chromosomes that have undergone rearrangements
vs. normal unicolor ones

28
Q

1) What is CGH (___ ___ ___)?

2) How does it work? [2]

A

1)CGH (Comparative Genome Hybridization) determines
abscence/presences of either ENTIRE chromosomes OR
microdeletions/duplications
2)Array CGH places fluorescently tagged Pt DNA and Control/normal Chromosomal DNA in a mix with corresponding DNA probes[either all the chromosomes or just specific chromosome probes]
*If pt DNA has Deletion=CONTROL DNA will bind to compliment DNA probe

  • *If pt DNa has DuPlication=PT DNA will bind to probe that has tht duplicated region as well
  • –>Microarray scanner then measures Fluorescent signals which produces linear plot of each probe in order in which their seq. should appear within a chromosome
29
Q

Which is has HIgher resolution but requires MORE DNA probes?
BAC array CGH or oligonucleotide array CGH?

A

Oligonucleotide array CGH requires MORE DNA probes to survey entire chromosome but resolution is HIGHER=easier identification for duplicated/deleted areas

30
Q

What is the advantage of using array CGH vs. FISH?

A 
array CGH(comparative genome hybridization) is better than FISH because it determines presence/absence of 
chromosomal microdeletions/duplications too small for metaphase FISH to pick up.
31
Q

Phenotypic Disorders and sx associated w/imprinted genes are mostly caused by ____________. The 2nd most frequent cause is _______ arising from _______

A

Phenotypic sx from imprinted genes mostly come from THE MICRODELETIONS IN 1 OF THE HOMOLOGOUS CHROMOSOMES.
2nd most freq. cause=UPD(uniparental disomy) which arise from nondisjunction

32
Q

What are the clinical/physical sx for Prader-Willi Syndrome?

A
  • Prader-Willi Syndrome
    1. Truncal Obesity
    2. hypogonadism
    3. small hands & short stature
    4. Mental retardation
33
Q

What are the clinical/physical sx for Angelman Syndrome?

A
  • **Angelman Syndrome
    1. wide stance/abnormal extremity positioning
    2. Spasticity with seizures
    3. short stature
    4. mental retardation
34
Q

1) What’s an important key to remember in regards to the alternative cause of Prader-Willi/Angelman syndrome??!
2) What are the STATS for this alternative cause?

A

1) 30%PW and 5%Angelman pts obtained the syndrme NOT FROM MICRODELETION of 15q11-13(like most who have it did) but from Uniparental disomy[UPD]
2) UPD of 30%PW pt= 2 copies of chromosome 15 from mom

UPD of 5%AngelMAN=2copies of chromo 15 FROM DAD(MAN)

35
Q

1) What is Genomic Imprinting?
2) How long does this last?

3)What’s the “catch” regarding Genomic imprinting?

A

1) Situation where a gene product is too harmful to be activated in BOTH MOM AND DADS chromosome so instead one parent passes on active version and the other passes on inactive version to child
2) Will last after fertilization and during postnatal devlopmnt

3)If Tayelor (sister) inherits an imprinted gene from our Dad/paternal then she has to 1st REVERSE that imprint in her germ cells so that she can pass that imprinted gene as a MATERNAL version to her kids

36
Q

MICRODELETION is the ____[MOST/least] frequent cause of Prader-Willi and Angelman syndrome. In regards to MICRODELETION:

1) Prader-Willi Syndrome is caused by___________
2) Angelman Syndrome is caused by_________

B: What is this phenomena called?

A

MICRODELETION=MOST FREQNT CAUSE OF PW AND ANGELMAN
1)Prad-Willi caused by microdeltn of DADS 15q11-q13 region

2)Angelman caused by microdeltn of moms 15q11-13 area

B: THIS IS CALLED “Parent-Of-Origin Microdeletion”effect

37
Q

What is UPD? [3]

A

*1)UPD (uniparental disomy) is 2nd most freq. cause of chromosomal Prader-Willi or AngelMan syndrome

*UPD involves receiving 1 extra copy (DOUBLE METHYLATION) of either moms 15th chromosome {30% PW population} or
1 extra copy of Dads(Man) 15th chromosome {5% AngelMan popultion}

—>Double Methylation of silenced copy leads to same effects as having deletion of the active copy

MCBG TEST 2!!! (13 decks)

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