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P Intergrated Y2 > GiM lectures 6,7,8 > Flashcards

GiM lectures 6,7,8 Flashcards

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1
Q

what is cytogenetics

A

study of chromosomes

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2
Q

The autosomes are which chromosomes?

A

1-22

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3
Q

X and Y are what type of chromsomes?

A

sex

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4
Q

What is conventional cytogenetics

A

metaphase chromosome analysis

- g banding

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5
Q

what is molecular cytogenetics

A

cytogenetic analysis at molecular resolution at all stages of cell cycle

  • fish
  • microarray CGH
  • next generation sequencing
  • MLPA
  • QF - PCR
  • qPCR
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6
Q

What are the phases of the cell cycle? (mitosis)

When are chromosomes most visible?

A

Most visible in metaphase

Interphase
Phrophase - line up
metaphase - spindle 
anaphase - separate
telophase - cell split starts
cytokinesis - 2 diploid cells
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7
Q

G Banded metaphase shows what?

A

karyotype
30,000 genes
550 bands

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8
Q

What are the types of cytogenetic abnormality

A

Numerical

Structural

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9
Q

How do cytogenetic abnormalities produce abnormal phentypes?

A

1) Dose effect (loss or gain)
2) disruption of gene
3) effect due to parental origin
4) position effect
- new chromosomal environment causes inappropiate gene function
5) unmasking recessive disorder

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10
Q

What are the numerical chromosome abnormalities

A

1) Aneuploidy - gain/loss trisomy/monosomy
2) Polyploidy - gain whole sets of chromosomes - triploidy, tetraploidy
3) mosaicism - diploidy and aneuploidy

diploidy - 2 copies of each chromosome

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11
Q

What causes errors at gametogenesis?

What is the result of errors in gametogenesis

A

increased maternal age

increased risk of aneuploidy

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12
Q

What are meiotic errors?

What percentage occur in meiosis 1 and meiosis 2?

A

Failure of chromosomes or chromatid separation

Meiosis 1 = 80-90% - chromosome non disjunction
Meiosis 2= 10-20%- chromatid non disjunction

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13
Q

What is the results of meiotic errors?

  • Meiosis 1
  • Meiosis 2
A

Meiosis 1 error = 2 disomic gametes, 2 nullisomic gametes

Meiosis 2 error = 1 disomic gamete, 1 nullisomic gamete, 2 normal gametes

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14
Q 
Triosmy 21 Clinical Features?
Frequency?
what % are miscarried?
Life expectancy?
Medical problems?
A

1/700
75% miscarried

Head - upwards slanting eyes, small noes, low set ears, protruding tongue, flat face, brachycephalic, short neck

Learning disabilities IQ30-60
Single palmar crease, 5th finger clinodactyly, wide sandal gap

Males infertile (women fertile)
Life expectancy 55-68yo

Increased risk of leukaemia
Alzheimers
Hypothyroid
Diabetes, hearing loss, arthritis.

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15
Q 
Edwards syndrome?
Frequency?
% miscarried
% survival to 1 year?
Clinical features?
Medical issues?
A

trisomy 18
1/6000 live births
95% miscarried
10% survive to 1

Microcephaly, low set ears, micrognathia, cleft lip and palate, clenched hands, rocker bottom feet, low birth weight, short sternum, severe mental retardation

90% congenital heart disease
congenital kidney abnormalities
umbilical hernias
eye abnormalities - cataracts

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16
Q

Patau Syndrome?
Frequency?
% miscarried
Clinical Features

A

Trisomy 13
1/12,000 live births
95% miscarried

Small at birth, severe mental retardation, microcephaly, holoprosencephaly defect of brain, palpebral figures slanted, retinal dysplasia, microphthaia, cleft lip and palate, low set abnormal ears, polydactyly, heart defect, abnormal genitals

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17
Q

What is Turners?
What is Klinefelters?

Give frequency for all possible karyotypes

A

Turners 45,X 1/2,500

Klinefelters
47,XXY 1/1000
47 XXX 1/1000
47,XYY 1/1000

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18
Q

What are the clinical features of turners?

A

Reproductive = infertile

  • Loss of ovarian function
  • NO puberty

Lymphatic
- Webbed neck, swollen hands/feet

Other
short stature, coartation of aroma, IQ lower/normal

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19
Q

What are the clinical feature of klinefelter

A

Infertility

  • testicular dysgenesis
  • gynaecomastia

Growth
- very long arms and legs
IQ - normal

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20
Q

What errors can occur at fertilisation?

A

Polyploidy

Molar pregnancy - double paternal, no maternal input

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21
Q 
What is Triploidy?
Karyotypes?
% of pregnancies?
% miscarried?
Frequency in live births?
A

Gain of whole set of chromosomes

69XXY, 69XYY, 69XXX
2% all pregnancies
99.9% miscarried
1/57000 live births

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22
Q

What are the origins of triploidy

A 
Dingy = 2 maternal 1 paternal
Diplospermy = 1 maternal 2 from one sperm
Dispermy = 1 maternal, 2 sperm
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23
Q

What is caused by double maternal chromosomes?

A

Tiny placenta
Growth delay
head saving macrocephaly

Materal genome focus on foetus

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24
Q

What is caused by double paternal chromosomes?

A

Large placenta
some growth delay in foetus

Paternal DNA for placenta

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25
what is a molar pregnancy?
Haploid sperm fertilises empty egg creating HAPLOID zygote. Haploid zygote "doubles up" to create a diploid zygote. DOUBLE paternal genome conception without and embryo results in MASSIVE cystic placenta
26
What errors occur at early cleavage? Where can errors occur? What are the possibly karyotypes?
Mosaicism - mitotic non-disjunction Errors can occur in second mitotic division Monosomy, trisomy, normal disomy
27
What are the consequences of mosaicism?
Variable phenotype, non identical twin, recurrence risk
28
What are the possible types of balanced chromosomal rearrangement?
Balanced 1) translocation - reciprocal - Robersonian 2) Inversion - pericentric - paracentric 3) Insertion
29
What is reciprocal translocation - how often does it occur what is the phenotype risk?
2 chromosome break and exchange a section 1/500 5-10% phenotype risk Has reproductive risk to offspring
30
What is a robertsonian translocation Frequency? Phenotype risk?
Whole arms fusion of ACROCENTRIC chromosomes 1/1000 no phenotype risk has reproductive risk
31
What are inversions? how often do they occur? Phenotype risk?
2 breaks within a chromosome then rejoin ``` pericentric = around centromere paracentric = swap within same limb ``` 1/1000 5-10% phenotype
32
What are unbalanced rearrangements? | How often do they occur?
1/2000 copy number variation - gain or loss commonest = deletions and duplication affect several genes
33
What are the types of deletions?
1) Interstitial deletion - segment lost from one arm | 2) Terminal deletion - end of arm lost
34
What are the types of duplications?
Direct - segment of chromosome copied twice ab,ab Indiverted - segment of chromosome is copied and inverted ab,ba
35
What is caused by deletions and duplications?
abnormal phenotype due to abnormal gene dosage
36
What is a ring chromosome
where the chromosome breaks at either telomere and rejoins to form a circle
37
How is G banding carried out?
``` Cell culture mitotic arrest hypotonic fixation tyrpsin and leishman's stain banding in AT and GC rich regions ```
38
What are molecular cytogenetic techniques?
Fluorescent in situ hybridisation (FISH) Multiplex ligation dependent probe amplification (MLPA) Microarray comparative genomic hybridisation (array CGH) Next generation sequencing Quantitative fluorescent PCR (QF-PCR) qPCR
39
What is the FiSH process
``` probe labelled with fluorochrome Denature DNA add target hybridise post hybridization washing visualisation under UV light ```
40
What are the types of probes?
unique sequence - segment within chromosome centromeric - centromere only paints - for whole chromosome
41
When are centromeric probes useful
counting numbers of chromosomes
42
What are the applications of FISH
``` copy number imbalance aneuploidy confirmation of g banding confirmation of array CGH identifying specific abnormalities in cancer ```
43
What is a copy number variation Consequences?
DNA segment with a variable copy no compared with reference genome Can give disease susceptibility OR resistance Low copy no of FCGR3B = high susceptibility to inflammatory autoimmune disorders High copy no CCL3L1 low HIV susceptibilty
44
What is MLPA
Multiplex Ligation-dependent Probe Amplification DNA-based Multiplex PCR Copy no. changes in up to 50 different genomic locations simultaneously Alternative to FISH
45
What is Microarray CGH
Genome-wide screen Hybridise sample & control DNA to a microarray “chip” 1000s of DNA spots (oligonucleotides) Genomic imbalances (copy number variants) at high resolution (10-10000x conventional cytogenetics) detection rates Replacing karyotyping as 1st line test
46
What are the advantages of array CGH
Early diagnosis -1st line test, reduces need for other tests and avoids the “diagnostic odyssey” High resolution = increased diagnostic hit rate Greater accuracy of location/size of imbalances Information on relevant genes
47
What are the disadvantages of array CGH
Dosage changes only – not balanced rearrangements or mutations Low level mosaics not detected Non-pathogenic & uncertain pathogenic changes detected Needs good quality DNA
48
What is Quantitative fluorescent PCR (QF-PCR
PCR amplification of short tandem repeats (STRs) [chromosome-specific, repeated DNA sequences] using fluorescent primers Products visualised & quantified as peak areas using an automated DNA sequencer
49
what is qPCR good for?
Quantitative comparison vs reference gene & normal control patient (amplify & quantify) Confirming small CNVs When FISH unsuitable Primer design
50
How does qPCR work?
Relative Quantitation (RQ) - compares difference in concentration between patient sample & normal control assessed by 2 different primer sets RQ value is expressed as a ratio relative to 1 - a deletion has an expected value of 0.5 & a duplication an expected value of 1.5
51
What samples can be used for cytogenetics? Which are appropriate for prenatal testing?
Blood Amniotic fluid Placenta Other foetal tissue Bone marrow Tumour Prenatal = amniotic fluid, chorionic villus
52
What leads to referrals for cytogenetic study?
Dysmorphic newborns, gender assignment, developmental problems, heart defect, reproductive problems, family studies
53
What is the recurrence risk of these robertsonian translocations 1) 46XXder(21:21)(q10:q10) parent carrier 2) 46XXder(14:21)(q10;q10),+21 male carrier? Female carrier?
1 = 100% ``` 2 = male carrier = 2% 2= female carrier = 12% ```
54
What is meiotic pairing
occurs in robertsonian translocation - trivalent = 14;21 combined chromatic formed in robertsonian translocation undergoes pachytene with its sister 21 and 14 chromatids forming a 3 chromatid structure. - a trivalent formation occur at PACHYTENE (pachytene is where two sister chromatids separate from each other and cross over) - Trivalent forms a chain during anaphase in meiosis 1 - centromeres move alternate poles
55
What % recurrent miscarriages are caused by a genetic problem?
2-3% of sufferers of recurrent miscarriages have balanced chromosome changes
56
When is prenatal diagnosis carried out?
Amniocentesis 16weeks chorionic villus biopsy 12weeks NIPT 12 weeks
57
In a balanced translocation what can be formed? | give and example of a balanced translocation?
a quadrivalent will be formed t(4;11) translocation
58
What are examples of NIPT (non invasive pre natal testing?) | What are the benefits and what does it test for?
Maternal blood sample Extract circulating free fetal DNA Assess aneuploidy of 13, 18, 21 (NGS) Risk for aneuploidy – invasive test to confirm Reduces no. of invasive tests
59
What are the indicators for prenatal diagnosis?
maternal age serum screen risk abnormal ultrasound scan (USS) FH/previous chromosome abnormality
60
How is cytogenetics performed on amniotic fluid?
1. Portion for DNA extraction (QF-PCR) 2. Separate cells from remaining fluid 3. Culture cells (7-14 days) if QFPCR result abnormal 4. G-banded analysis
61
How is cytogenetic performed on chorionic villi?
1. Separate maternal from foetal tissue 2. QF-PCR 3. Culture cells (7-14 days) if QFPCR result abnormal 4. G-banded analysis
62
what are the advantages and disadvantages of array CGH and prenatal diagnosis
Replacement of cell culture if abnormal scan Advantages Increased resolution Higher detection rate Disadvantages Ethical, eg small duplication & associated autism Need parental follow up
63
What translocation can cause leukaemia
T(9;22) IN CML "philadelphia chromosome abl gene (9) fuses to bcr gene (22) - to create an abnormal protein
64
What forms of cytogenetics can be used on solid tumours?
Fresh - FISH/gBanding (1-20days) Archived paraffin embedded tissues - FISH or genotyping
65
What does the presence of MYCN gene amplification in a neuroblastoma mean
poor prognosis | high dose chemo recommended

P Intergrated Y2 (13 decks)

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