Chromosome Abnormalities

Question 1

Chromosome analysis

Answer 1

• METAPHASE chromosome analysis
• need living cells for in vitro growth (bone marrow, blood, amnionic fluid, cvs and solid tissue) different samples yield different length chromosomes
• check number and pairs of chromosomes to check that the bandings match

Question 2

KARYOTYPING

Answer 2

• systematic sorting of chromosomes
• metaphase chromosomes are stained, paired up and then grouped together
• abnormalities described using standard nomenclature ISCN

Question 3

Chromosome morphology

Answer 3

• chromosomes have 2 arms (petite - p arm and long - q arm)
  Metacentric
• arms of almost equal length
  Sub-metacentric
• p arm is shorted than the q arm
  Acrocentric
• p arm is shorted than the q arm - no longer connected
• no euchromatic material in the p arm (no genes of importance)

Question 4

Chromosome groups

Answer 4

• chromosomes are grouped according to size and shape

Question 5

G-banding staining

Answer 5

Trypsin digests the proteins
Stained with Romanowski type dye
Produces dark and light bands
- dark G+ve bands are AT rich (gene poor)
- light G-ve bands are GC rich (gene rich)
Dark and light bands are numbered according to international convention

Question 6

Automated karyotyping

Answer 6

The chromosomes are analysed and then paired up automatically on the screen

Question 7

Cytogenetic analysis (e.g. KARYOTYPING)

Answer 7

• accurate diagnosis/prognosis of clinical problems
  (Identify the syndrome associated with abnormality, account for phenotype, account for pregnancy losses)
• better clinical management
  (e.g. hormone treatment for Klinefelter syndrome XXY)
• assess future productive risk
  (Risk of live bind abnormal child, previous downs pregnancy increases the risk of another by 1%)
• prenatal diagnosis
  (risk of affected pregnancy and/or planning for management at birth)

Question 8

Referral reasons

Answer 8

Constitutional abnormalities 
- prenatal diagnosis 
- birth defects 
- abnormal sexual development 
- infertility 
- recurrent fetal loss
Acquired abnormalities 
- leukaemias 
- solid tumours 
- specific translocations/abnormalities can give prognostic information

Question 9

Prenatal diagnosis methods

Answer 9

Chorionic villus sampling
- 11-12 weeks gestation (1.2% increased risk of miscarriage)
Amniocentesis
- 15 weeks onwards (0.8% miscarriage risk)

Question 10

Prenatal diagnosis

Answer 10

• maternal serum screening for Down’s syndrome
• first trimester screening - biochemical and ultrasound scan
• FH chromosome abnormality
• abnormal ultrasound scan (cystic hygroma, cleft lip/palate, heart abnormalities
• DNA studies

Question 11

Birth defects

Answer 11

Dysmorphism
Congenital malformations
Mental retardation
Development delay (abnormal behaviour, learning difficulties)
Specific syndromes (Down syndrome - trisomy 21, williams syndrome - deletion 7q11.23, digeorge syndrome - deletion 22q11.2)
Aneuploidy - loss or gain off a whole chromosome (due to errors at cell division in meiosis)
Trisomies - Down syndrome +21, Patau syndrome +13, Edwards +18
Monosomies - Turner syndrome 45,X (only full monosomy will be viable - inactivation of X)

Question 12

Polyploidy

Answer 12

• gain of a whole haploid set of chromosomes (3n -69,XXX)
  Most common cause of polyploidy is polyspermy - one egg fertilised by more than one sperm
  Triploidy occurs in 2-3% of all pregnancies and ~15% of all miscarriages - term deliveries die shortly after birth

Tetraploidy is rarer 1-2% but tetraploid cells are often found at prenatal diagnosis as a cultural artefact
Diploid/triploid mosaicism (same genetic position with different genetic makeup) seen in live births

Question 13

Aneuploidy (abnormal number of chromosomes in a cell e.g. 45 or 47 when there should be 46)

Answer 13

Originates from non-disjunction (failure of sister chromatids or homologous chromosomes to separate properly during cell division)
Forms gametes with a missing chromosome and an extra chromosome (which chromosomes involves will influence viability)
Can occur during mitotic cell division (causes mosaicism)

Question 14

DNA packaging

Answer 14

• DNA is wrapped around an octamer of histones (166bp per octamer) - protein structure = chromatin
  Chromatin can switch back and forth between active (methylated) and inactive (demethylated)
  epigenetic modification - changes to DNA methylation but not to the DNA sequence

Question 15

Anaphase lag

Answer 15

• chromosomes can be left behind at cell division because of defects in spindle function or attachment to chromosomes
• the lagging chromosome may be lost entirely in mitosis or meiosis

Question 16

Trisomy 21

Down syndrome

Answer 16

Frequency 1:650-1000
- hypotonia (reduced muscle strength) 
- characteristic facial features 
- intellectual disability 
- heart defects 
- increased prevalence of leukaemia and early Alzheimers
-

Question 17

Trisomy 18

Edwards syndrome

Answer 17

1:6000 - female predominance (maternal meiosis II error) modal lifespan 5-15 days 
Diagnosis made prenatally 
- small lower jaw
- prominent occiput (back of the head) 
- low set ears
- rocker bottom feet 
- overlapping fingers

Question 18

Trisomy 13

Patau syndrome

Answer 18

1:12000
Multiple congenital abnormalities 
Polydactyly - more fingers or toes 
Holoprosencephaly - facial disfigurement
Majority die in neonatal period

Question 19

Turner syndrome 45,X

Answer 19

1: 2500
- puffy feet
- redundant skin at the back of the neck
- Short statue, heart defects, mild learning difficulties, neck webbing, infertility

Question 20

X chromosome inactivation

Answer 20

• only one X chromosomes is active in a human cell
• X inactivation ensure that individuals have same X chromosome that is active
  Males have two pseudo-autosomal regions (PAR1 and PAR2)

Question 21

Mosaicism

Answer 21

Presence of two or more cell lines in an individual (

- usually caused by mitotic non-disjunction