Chromosomal Abnormalities I Flashcards
Describe packaging of chromosomes
Chromosomes usually exists as chromatin
DNA double helix bounds to histones
Octamer of histones form nucleosome
Describe structure of euchromatin and its function
Euchromatin
Extended state, dispersed through nucleus
Allows gene expression
Describe structure of euchromatin and its function
Heterochormatin
Highly condensed, genes not expressed
G1 - describe what happens
G1 = Cell makes a variety of proteins needed for DNA replication
S - describe what happens
S = synthesis; chromosomes are replicated so that each chromosome now consists of two sister, identical chromatids
G2 - describe what happens
G2 – synthesis of proteins especially microtubules
Some cells don’t replicate; some are senescent.
Metacentric - define and describe which ones
Metacentric
p & q arms even length
1-3, 16-18
Submetacentric - define and describe which ones
Submetacentric
p arm shorter than q
4-12, 19-20, X
Acrocentric - define and describe which ones
Acrocentric
Long q, small p
p contains no unique DNA
13-15, 21-22, Y
Detecting chromosomal changes
Numerical = Can detect through traditional karyotyping, FISH, QF-PCR, NGS
Structural = Can detect through traditional karyotyping, FISH
Haploid - define
one set of chromosomes (n=23) as in a normal gamete.
Diploid - define
cell contains two sets of chromosomes (2n=46; normal in human)
Polyploid - define
multiple of the haploid number (e.g. 4n=92)
Aneuploid - define
chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47)
Numerical Abnormalities - list
Trisomy
Monosomy
Mosaicism
Disjunction - define
Pulling apart at anaphase = disjunction
How does aneuploidy arise?
Primary mechanism = Non-disjunction
Mosaicism - define
Presence of two or more genetically different cell lines derived from a single zygote
Mosaicism - describe mechanisms
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
Monosomy - cause
Full monosomy arise by NDJ
Partial monosomy (microdeletion syndromes) far more common – mechanism different
Monosomy - which type is R.V. common
Relatively common sex chromosome monosomy = Turner’s
How does Turner’s (45,X) arise?
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
Nullisomic gametes - effects of possible combinations
Nullisomic gametes
+ X chr = XO = Turner’s (physically female)
+ Y chr = lethal
Disomic gametes - effects of possible combinations for XX
XX:
+ X chr = XXX = triple X syndrome
+ Y chr = XXY = Klinefelter’s (physically male)
Disomic gametes - effects of possible combinations for XY
XY:
+ X chr = XXY = Klinefelter’s
+Y chr = XYY = XYY syndrome
Numerical abnormalities - types
Types (all can be mosaic)
Autosomal
Trisomy 13, 18, 21
Sex chromosomes
XO, XXY, XYY
Numerical abnormalities - mechanism
Mechanism:
Nondisjunction
Anaphase lag
Anaphase lag - define
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.
Forming a karyotype
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
Chorionic villus sampling (CVS) - define
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.
Chorionic villus sampling (CVS) - +ves/-ves
11-14 weeks
Miscarriage rate 0.5% to 1%
maternal contamination
transverse limb defects
Amniocentesis - +ves/-ves
> 16 weeks
extraction of amniotic fluid
Biochemical diagnosis possible
miscarriage risk (0.5-1%)
Giemsa - use
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.
Giemsa - Line-up based on
Size
Banding
Centromere position
Why chromosome bands?
Chromatin:
2 different sorts: euchromatin & heterochromatin
Euchromatin = GC-rich; loosely packed; genes active
Heterochromatin = AT-rich; tightly packed; genes inactive
Stain differently
Most common bands?
Giemsa bands
Foetal testing - invasive vs non-invasive
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
Trisomies - advantages
SAFE TEST – Trisomies 13, 18, 21
Available privately ~ £400
But now free at St George’s!
Down syndrome – clinical features
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
Down Syndrome - causes
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
Patau syndrome (risomy 13) - clinical features
~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
Hypotelorism define
Hypotelorism=abnormally close eyes
Holoprosencephaly - define
Holoprosencephaly – forebrain doesn’t divide properly-causes facial malformations as well
Post-axial - define
Post-axial=lateral side of foot or hand (little finger side)
Edwards syndrome (trisomy 18) - clinical features
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
Micrognathia - define
Micrognathia = small lower jaw
Palpebral fissures - define
Palpebral fissures - gap between eye lids
Survival in Edwards syndrome
30% die by 1 month
50% die by 2 months
90% by 1 year
Sex chromosome aneuploidies - incidence
Incidence: male 1/400
female 1/600
all autosomal 1/700
Sex chromosome aneuploidies vs autosomal aneuploidy
Phenotype often less severe than autosomal aneuploidy
Turner syndrome - clinical features
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
45X/46XY mosaicism - define
usually normal male but with potential for gonadoblastoma
Isochromosome Xq effect
Mosaicism with ring or isochromosome Xq = variant turner syndrome
Klinefelter (47,XXY) - clinical features
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
Klinefelter (47,XXY) - effects
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
