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B312 > L6, Chromosomal Disorders > Flashcards

L6, Chromosomal Disorders Flashcards

1
Q

Describe the preparation of a karyotype:

A
  1. 0.5ml blood in 5ml culture medium
  2. Add phytohemagglutinin (stimulates lymphocytes to divide)
  3. Culture 48-72 hrs
  4. Add colcemid (arrests cells in metaphase)
  5. Culture briefly; add hypotonic KCl to swell cells; fix in 3:1 methanol:acetic acid; drop onto microscopic slide
  6. Brief digestion with trypsin, stain with Giemsa
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2
Q

Features of a normal karyotype:

A
  • 23 chromosomes
  • xx in females, xy in males
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3
Q

What is G-banding:

A
  • Distinctive pattern produced by Giemsa staining
  • G-bands occur in heterochromatin (AT rich so stains well)
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4
Q

Labelling conventions for chromosome bands:

A
  • Short arm: p
  • Long arm: q
  • Domains 1, 2 etc. radiate out from centromeres
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5
Q

Polyploidy in humans vs other species:

A
  • Extra complete sets of chromosomes
  • Very rare in humans
  • Triploid can arise when an egg is fertilised by 2 sperms; rarely survive to term, usually have severe defects and live only minutes if born
  • Tetraploidy virtually not observed in live births
  • Salamanders, frogs and leaches are all polyploid
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6
Q

Aneuploidy: Examples, relevance to human births

A
  • 2N-1: Monosomy
  • 2N+1: Trisomy
  • Estimated half of human conceptions are aneuploid but most die early on before development
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7
Q

What is non-disjunction

A
  • Chromosome fails to separate, either in meiosis I or II
  • Demonstrate: FCs
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8
Q

List the 3 viable autosomal aneuploidies:

A
  • Trisomy 21 (Downs syndrome) -> Survival to adulthood
  • Trisomy 13 (Patau syndrome)
  • Trisomy 18 (Edward syndrome)
  • All monosomies are non-viable
  • 13 and 18 -> severe, multi-system effects; survival to adulthood prohibited
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9
Q

Visible characteristics of Downs syndrome:

A
  • Wide skull, flattened at back
  • Tongue may be furrowed and protruding
  • ‘Simian’ crease on palms of hands and soles of feet
  • Epicanthic folds above eyes
  • Brushfield spots on the iris
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10
Q

Clinical characteristics of DS:

A
  • Physical and mental retardation
  • Increased likelihood of congenital heart defects
  • 15X increased chance of leukaemia
  • Susceptibility to AD (50% prevalence in DS populations by age 60)
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11
Q

Patau syndrome: Overview

A
  • aka trisomy 13
  • 1 in 20,000 live births
  • Cleft lip and palate
  • Physical and mental retardation
  • Defects in multiple organ systems
  • Most die within first year
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12
Q

Edwards syndrome: Overview

A
  • 1 in 6,000 live births
  • Clenched fist with first and fourth fingers overlapping the middle two
  • Rocker bottom feet
  • Heart kidney and other internal abnormalities
  • Median lifespan 5-15 days
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13
Q

List the sex chromosome aneuploidies:

A
  • XO: Turner syndrome -> Viable
  • XXY: Klinefelter
  • XXX: Metafemale
  • XYY
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14
Q

Typical outcomes in sex chromosome aneuploidies:

A
  • Generally more concerned with male infertility than survival
  • Extra X’s tend to be inactivated
  • XXX and XXY relatively mild to the point of going undiagnosed -> often reduced fertility, compounded by number of extra X’s
  • DSD: Proper term for disorders of sex development
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15
Q

Turner syndrome: Overview

A
  • 1 in 2,500 live births
  • Poorly developed secondary sexual characteristics -> develop as girls but sterile
  • Hormone therapy can generally be used to overcome secondary sex issues (rudimentary ovaries) but not infertility itself
  • Short stature, bone malformations and webbed neck
  • Puffy hands and feet at birth
  • Structural heart abnormalities reported
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16
Q

Klinefelter syndrome overview:

A
  • Occurs in around 1 per 1000 live male births
  • Male genitalia
  • Excessive height at puberty
  • Tendency to some female secondary sex characteristics (breasts, fat and pubic hair distribution)
  • Testes small and underdeveloped -> low fertility (few to no sperm)
17
Q

Chromosome rearrangements: List the 5 types

A
  • Deletion
  • Duplication
  • Inversion
  • Nonreciprocal translocation (one way)
  • Reciprocal translocation (both ways)
18
Q

Congenital disorders associated with Chromosome deletions (with chr. bands)

A
  • Cri-du-chat: 5p15
  • Prader willi: 15q11-13
  • Angelmann: 15q11-13
  • Wolf-Hirschorn: 4p16
  • Miller-Dieker: 17p13
  • Di-george: 22q11
19
Q

Cri-du-chat: Overview

A
  • 1 in 50,000 live births
  • Distinctive cat cry in babies
  • Defects in glottis and larynx, wide face and saddle nose
  • Physical and mental retardation
  • Range of severity which depends on extent of deletion
  • Low mean survival time
  • Adolescents have normal puberty and are fertile
20
Q

How do chromosome rearrangements come about?

A
  • Crossing over between repetitive regions of DNA
  • Adjacent sites on same strand -> looping out -> deletion
  • Sites on neighbouring strands -> non reciprocal translocation-> duplication in one strand and deletion in other
  • Adjacent sites on same strand -> inversion
  • Sites on neighbouring strands -> reciprocal translocation
21
Q

How does translocation come about? Types?

A
  • Crossing over -> tetravalent
  • Both balanced and unbalanced translocations can come about
  • Unbalanced are highly unlikely to be viable whereas balanced can often go unnoticed
  • If a terminated foetus is found to have this unbalanced karyotype, checking the parent for balanced translocation can be informative of their fertility
22
Q

When is giemsa staining useful in diagnosing chromosomal disorders?

A
  • Best for aneuploidies and large deletions or duplications
23
Q

Drawbacks of giemsa staining for diagnosing chromosomal disorders:

A
  • Time consuming
  • Low sensitivity -> can’t detect rearrangements smaller than 5Mbp
24
Q

Alternatives to giemsa staining in diagnosing chromosomal disorders:

A
  • Fluorescent in situ hybridisation (FISH)
  • Array comparitive genomic hybridisation (Array CGH)
  • Single nucleotide polymorphism (SNP) profiling
  • Whole genome sequencing (non invasive pre-natal diagnosis)
25
Q

+ Two Further examples of microdeletions:

So many witchy boils

A
  • Smith-Magenis
  • Williams-Beuren
  • Occur spontaneously because of recombination between repeated sequences (e.g. transposable elements)
26
Q

Describe the FISH method:

A
  • Spread chromosomes on slide
  • Denature DNA in situ
  • Hybridise with fluorescently labelled probe corresponding to region of interest
  • Wash off unbound probe
  • Stain with DAPI (DNA intercalating stain)
  • View under fluorescent microscope
  • Need to include control probe for unaffected region of same chromosome (different colour)
27
Q

Probes commonly used in routine FISH testing:

A
  • 13, 18, 21 -> Trisomies
  • X and Y -> Sex chromosome aneuploidies
27
Q

2 key limitations of FISH:

A
  • Small deletions or duplications cannot be detected
  • Can only detect the region corresponding to the probe - requires prior knowledge of structures etc
28
Q

Array CGH: Protocol

A
  • DNA from patient and control extracted and labelled with different fluorescent dyes
  • DNAs mixed together in equal quantities and hybridised to the microarray
  • Slide washed and scanned
  • Most spots will have equal red and green fluorescence
  • Deletions or duplications represented by diminished or excessive green fluorescence across several spots (quantified using software -> plot)
29
Q

SNP arrays: Overview

A
  • Microarray consisting of thousands of oligonucleotide pairs spanning genome, each pair differing at a single base
  • Hybridise with fluorescently labelled DNA from patient -> exact match required
  • Signal from both variants added together
  • Identifying regions in genome where signal is equivalent to single variant
  • Quite common and cheap, doesn’t necessitate control DNA although they are still often used 9e.g. comparison to parents SNP array profiles)
30
Q

NIPT/NIPD: Overview

What is it used for, when can it be carried out from?

A
  • Up to 10% of free DNA in maternal serum is foetal
  • Free DNA (minimum 5% foetal DNA required) is amplified and sequenced by NGS -> relative number of sequence reads is used to measure chromosome number
  • Can be carried out from 9 weeks
  • May be used to detect aneuploidies, sex of foetus and some single gene mutations
31
Q

+ Chromosomal abnormalities occur in … % of births

A
  • About 1%
32
Q

+ Example of congenital condition which is not genetic in origin or a de novo mutation

A
  • Teratogenic effects of thalidomide
  • Causes limb abnormalities and other issues
  • Widely prescribed in 1950s and early 1960s to treat morning sickness in pregnancy
33
Q

+ Triple X syndrome

A
  • Around 1 in 1000 female live births
  • Often go unnoticed; few physical abnormalities
  • Often shorter than average
  • High prevalence in mental institutions (1 per 250 as of 1994)
  • Early menopause is almost universal for the condition
  • At risk for speech delays, learning disabilities, neuromotor impairment and mental illness
  • Extra X typically originates from errors in maternal meiosis (particularly meiosis I) -> correlated with advanced maternal age
34
Q

+ 46, XX testicular DSD: How are these patients male with XX chromosomes?

A
  • Generally have Y-chromosome sequence somewhere in their genome -> usually the SRY gene (male-determining factor)
  • Commonly, this gene would be translocated onto the paternal X chromosome (SRY on an autosome is quite rare)
35
Q

+ What about chromosomes 21, 13 and 18 might make them viable as trisomies?

A
  • They contain some of the lowest gene densities
  • An addition in these chromosomes is thus conferring the minimal amount of extra genes

B312 (15 decks)

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