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Fundamentals of P > Chromosomal Abnormalities I > Flashcards

Chromosomal Abnormalities I Flashcards

1
Q

Describe packaging of chromosomes

A

Chromosomes usually exists as chromatin
DNA double helix bounds to histones
Octamer of histones form nucleosome

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2
Q

Describe structure of euchromatin and its function

A

Euchromatin
Extended state, dispersed through nucleus
Allows gene expression

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3
Q

Describe structure of euchromatin and its function

A

Heterochormatin

Highly condensed, genes not expressed

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4
Q

G1 - describe what happens

A

G1 = Cell makes a variety of proteins needed for DNA replication

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5
Q

S - describe what happens

A

S = synthesis; chromosomes are replicated so that each chromosome now consists of two sister, identical chromatids

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6
Q

G2 - describe what happens

A

G2 – synthesis of proteins especially microtubules

Some cells don’t replicate; some are senescent.

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7
Q

Metacentric - define and describe which ones

A

Metacentric
p & q arms even length
1-3, 16-18

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8
Q

Submetacentric - define and describe which ones

A

Submetacentric
p arm shorter than q
4-12, 19-20, X

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9
Q

Acrocentric - define and describe which ones

A

Acrocentric
Long q, small p
p contains no unique DNA
13-15, 21-22, Y

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10
Q

Detecting chromosomal changes

A

Numerical = Can detect through traditional karyotyping, FISH, QF-PCR, NGS

Structural = Can detect through traditional karyotyping, FISH

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11
Q

Haploid - define

A

one set of chromosomes (n=23) as in a normal gamete.

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12
Q

Diploid - define

A

cell contains two sets of chromosomes (2n=46; normal in human)

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13
Q

Polyploid - define

A

multiple of the haploid number (e.g. 4n=92)

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14
Q

Aneuploid - define

A

chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47)

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15
Q

Numerical Abnormalities - list

A

Trisomy

Monosomy

Mosaicism

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16
Q

Disjunction - define

A

Pulling apart at anaphase = disjunction

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17
Q

How does aneuploidy arise?

A

Primary mechanism = Non-disjunction

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18
Q

Mosaicism - define

A

Presence of two or more genetically different cell lines derived from a single zygote

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19
Q

Mosaicism - describe mechanisms

A

2 mechanisms:

Post-zygotic nondisjunction, i.e. mitotic non-disjunction = All 2n to mixture of 2n and 2n+1

Anaphase lag, i.e. trisomic rescue = All 2n+1 to mixture of 2n+1 and 2n

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20
Q

Monosomy - cause

A

Full monosomy arise by NDJ

Partial monosomy (microdeletion syndromes) far more common – mechanism different

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21
Q

Monosomy - which type is R.V. common

A

Relatively common sex chromosome monosomy = Turner’s

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22
Q

How does Turner’s (45,X) arise?

A

Nullisomic gametes fertilised with a sperm carrying an X chromosome will be XO (Turners)

Nullisomic gametes fertilised with a sperm carrying a Y chromosome will be YO

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23
Q

Nullisomic gametes - effects of possible combinations

A

Nullisomic gametes
+ X chr = XO = Turner’s (physically female)
+ Y chr = lethal

24
Q

Disomic gametes - effects of possible combinations for XX

A

XX:

+ X chr = XXX = triple X syndrome
+ Y chr = XXY = Klinefelter’s (physically male)

25
Q

Disomic gametes - effects of possible combinations for XY

A

XY:

+ X chr = XXY = Klinefelter’s
+Y chr = XYY = XYY syndrome

26
Q

Numerical abnormalities - types

A

Types (all can be mosaic)

Autosomal
Trisomy 13, 18, 21

Sex chromosomes
XO, XXY, XYY

27
Q

Numerical abnormalities - mechanism

A

Mechanism:

Nondisjunction
Anaphase lag

28
Q

Anaphase lag - define

A

Sister chromatids do not properly separate from each other because of improper spindle formation

The chromosome or chromatid does not properly migrate during anaphase and the daughter cells will lose some genetic information.

29
Q

Forming a karyotype

A 
Take 5 mL venous blood
Add phytohemagglutinin + culture medium
Culture at 37 degrees celsius for 3 days
Add colchicine and hypotonic saline
Cells fixed 
Spread cells onto slide by dropping 
Digest with trypsin and stain with giemsa
Analyze metaphase spread
= karyotype
30
Q

Chorionic villus sampling (CVS) - define

A

a prenatal test that is used to detect birth defects, genetic diseases

A small sample of cells (called chorionic villi) is taken from the placenta where it attaches to the wall of the uterus.

31
Q

Chorionic villus sampling (CVS) - +ves/-ves

A

11-14 weeks

Miscarriage rate 0.5% to 1%

maternal contamination

transverse limb defects

32
Q

Amniocentesis - +ves/-ves

A

> 16 weeks
extraction of amniotic fluid
Biochemical diagnosis possible
miscarriage risk (0.5-1%)

33
Q

Giemsa - use

A

Giemsa highlights heterochromatic regions which are less likely to contain genes.

But the crucial thing is that the banding can be used to differentiate between chromosomes ant to compare chromosomes.

34
Q

Giemsa - Line-up based on

A

Size
Banding
Centromere position

35
Q

Why chromosome bands?

A

Chromatin:

2 different sorts: euchromatin & heterochromatin
Euchromatin = GC-rich; loosely packed; genes active
Heterochromatin = AT-rich; tightly packed; genes inactive
Stain differently

36
Q

Most common bands?

A

Giemsa bands

37
Q

Foetal testing - invasive vs non-invasive

A

Invasive
Amniocentesis (14-20 wks, amniotic fluid)
Chorionic villus sampling (CVS) (11-14 wks, placental cells)

Non-invasive
Cell free foetal DNA (cffDNA): DNA fragments in maternal plasma (10 wks onwards)
Actually for trisomies still need confirmation with amnio/CVS

38
Q

Trisomies - advantages

A

SAFE TEST – Trisomies 13, 18, 21
Available privately ~ £400
But now free at St George’s!

39
Q

Down syndrome – clinical features

A 
1 in 650-1000 live births
Most common cause of mental retardation
Hypotonia, particularly in newborn period
Developmental delay
Cardiac abnormalities
GI abnormalities
Acute Lymphocytic Leukaemia/Acute Myeloid Leukaemia – 10-20 x relative risk
Conductive hearing loss
Features of Alzheimer’s >40 years
40
Q

Down Syndrome - causes

A

95% patients non-disjunction (usually maternal meiosis I)
5% Robertsonian translocation involving chromosome 21
~2% mosaic (ie only some cells contain an extra chromosome)

‘Older Egg Model’ – maternal age effect

41
Q

Patau syndrome (risomy 13) - clinical features

A

~1 in 10 000 live births

Midline defects

  • Hypotelorism
  • Holoprosencephaly
  • Midline cleft lip/palate
  • Scalp defects

Post axial polydactyly
Heart defects/renal abnormalities
Survival – most die by 1 month

42
Q

Hypotelorism define

A

Hypotelorism=abnormally close eyes

43
Q

Holoprosencephaly - define

A

Holoprosencephaly – forebrain doesn’t divide properly-causes facial malformations as well

44
Q

Post-axial - define

A

Post-axial=lateral side of foot or hand (little finger side)

45
Q

Edwards syndrome (trisomy 18) - clinical features

A 
Incidence ~1 in 6000 live births
Intrauterine growth retardation
Micrognathia
Cleft lip +/- palate
Short palpebral fissures
Fixed flexion deformities of fingers
Heart defect >95%
Inguinal/diaphragmatic herniae
Renal malformations
46
Q

Micrognathia - define

A

Micrognathia = small lower jaw

47
Q

Palpebral fissures - define

A

Palpebral fissures - gap between eye lids

48
Q

Survival in Edwards syndrome

A

30% die by 1 month
50% die by 2 months
90% by 1 year

49
Q

Sex chromosome aneuploidies - incidence

A

Incidence: male 1/400
female 1/600
all autosomal 1/700

50
Q

Sex chromosome aneuploidies vs autosomal aneuploidy

A

Phenotype often less severe than autosomal aneuploidy

51
Q

Turner syndrome - clinical features

A 
Incidence 1/4000 female births
45X0 or mosaic (45X0/46XX)
Raised nuchal translucency
At birth: 
- oedema of hands and feet
- Neck webbing
- coarctation of aorta
- renal malformation
Short stature
Infertility secondary to gonadal dysgenesis
Intellectually normal
52
Q

45X/46XY mosaicism - define

A

usually normal male but with potential for gonadoblastoma

53
Q

Isochromosome Xq effect

A

Mosaicism with ring or isochromosome Xq = variant turner syndrome

54
Q

Klinefelter (47,XXY) - clinical features

A

Incidence 1/1000 male live births
Phenotype mild and variable – some cases undetected
Barr body present
NDJ paternal meiosis I (50%), others NDJ maternal meiosis or zygotic mitotic error (mosaic)
Variants: 48,XXYY, 48,XXXY etc

55
Q

Klinefelter (47,XXY) - effects

A

May present prenatally, during childhood with behavioural problems, or adulthood with infertility
Tall stature
Eunachoid body habitus
Some behavioural and minor learning difficulties
Lack of secondary sexual characteristics – treat with testosterone
Infertility

Fundamentals of P (62 decks)

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