Chromsome Disorders Flashcards
How many pairs of chromosomes?
22 autosomal
1 sex
Plus mitochondrial genome
What is a gene?
Specific stretch of DNA where sequence contains genetic instructions
How are genes arranged on chromosomes?
Linear order
Chromosomes have a short arm and long arm. True/ False
True
Function of the centromere:
- joins sister chromatids
- essential for chromosome segregation at cell division
What are light bands of chromosomes?
Replicate early in S phase
Less condensed chromatin
Transcriptionally active
Gene and GC (bases) rich
What are dark bands on chromosomes?
Replicate late
Contain condensed chromatin
AT (base) rich but not gene rich
Telomere on chromosome?
DNA and protein cap
Ensures replication to tip
Tether to nuclear membrane
How chromosomes are examined?
Karyotype
Florescent in situ hybridisation (FISH)
Array CGH
How karyotypes are produced:
- 5ml of venous blood
- Separate off rbc
- add culture medium to white cell suspension
- incubate
- colchicine added, separate off white cells
- hypotonic saline added
- cells fixed
…..
How are specific chromosomes recognised?
Via their banding pattern
How to examine karyotypes?
- Count number of chromosomes and check if any extra
- Look for copy no. Variants or sections of dna missing
What types of chromosome abnormalities are there?
- Chromosome number
- Chromosome structure
- Classified according to which cells they disrupt:
- constitutional (all cells of the body)
- somatic (only certain cells)
How to name and classify abnormalities?
- Total number of chromosomes
- Sex chromosomes constitution
- Abnormalities/ variants
E.g. trisomy syndrome
47, XX, +21
Extra chromosome and male
Types of abnormalities of chromosome number:
- Aneuploidy - changes in a single chromosome number (haploid set)
- Polyploidy - changes in overall chromosome number (more than 2 complete sets of chromosome)
Trisomy?
Aneuploidy - Additional chromosome
Monosomy?
Aneuploidy - missing chromosome
Triploidy?
Polyploidy - additional set of chromosomes in the cell for total of 69 rather than normal 46
Tetraploidy?
Polyploidy - when an affected individual has four copies of each chromosomes instead of 2
96 chromosomes
Trisomy 21?
Known as “Down syndrome”
Extra copy of chromosome 21. 3 in total.
How does a trisomy occur?
Non dysjunction during meiosis II
Sister chromatids don’t separate equally
What is disomic nullisomic?
Produced after non disjunction
Incorrect number of chromosomes in gametes
What are oocytes?
All women born with them
Each remains in maturation arrest at the crossing over stage until ovulation
Each month 1 oocyte ovulated and completes meosis
Parental origin of meiotic error leading to trisomies (associated with increase in maternal age):
Older the woman the older the oocytes
Accumulating effects on the primary oocytes during this phase may damage the cells spindle formation and repair mechanisms
- predisposing them to non dysjunction
Which has more severe consequences?
Reducing the gene copy
Increasing the gene copy
Reducing the gene copy
Most frequent numerical autosomal anomalies in liveborns:
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18)
Patau syndrome (trisomy 13: 47,XX,+13)
Most frequent numerical sex chromosome anomalies in liveborn:
Turner syndrome female: 45,X
Klinefelters syndrome male: 47,XXY
Most frequent numerical anomalies in liveborns including all chromosomes?
Triploidy 69 chromosomes
Features of trisomy 21:
Epicanthic folds
Depressed nasal bridge
Profound neonatal hypotonia
Exomphalos
Single palmar crease
Brushfield spots
Up slanting palpebral fissures
Cataract
3 types of genetic basis (causes) of Down syndrome:
- 95% people ave 3 separate copies of chromosome 21 (trisomy 21)
- 4% have extra copy of chromo 21 due to Robertsonian translocation
- 1% have mosaicism with normal and trisomy 21 cell lines. Occurs after fertilisation. Non dysjunction happens in mitosis after development.
What is edwards syndrome?
Trisomy 18
1 in 3000 births
Multiple malformations (especially heart, kidneys)
How does 3 copies of chromosome 21 cause the features of Down syndrome?
No mutations so protein still the same
- “Gene dosage effect” - features of syndrome caused by 1.5 times amount of specific gene product from chromo 21
- “Amplified developmental instability” - features of syndrome cause by overall effect of imbalance on development
Patau syndrome?
Trisomy 13
1 in 5000 births
Multiple malformations
Affects midline structures paticularly incomplete lobation of the brain
Cleft lip
Congenital heart disease
All autosomal abnormalities have a low survival rate except for:
Trisomy 21
Klinefelter syndrome?
1 in 1000 male births
Infertility
Poorly developed secondary sexual characteristics
Tall stature
Mild learning problems
Turner’s syndrome?
45, X
25-50 in 100,000 females
Short stature
Primary gonadal failure
Can affect multiple organ systems cardiac, thyroid, renal
Are sex or autosomal chromosome abnormalities worse?
Sex chromosome abnormalities are worse but less severe than autosomal
What is Aneuploidy usually caused by?
Caused by the results of meiotic non disjunction related to maternal age
Risk of recurrence is therefore low and will be related to age of the mother
What is genetic counselling?
Types of Aneuploidy (trisomies):
Trisomy 21 - Down syndrome
Trisomy 18 - edwards syndrome
Trisomy 13 - Patau syndrome
Classification of abnormalities of chromosome structure:
Translocations
- reciprocal/ robertsonian
Deletion
Duplication
Inversion
Ring chromosomes
Marker chromosomes
Complex rearrangements
What is robertsonian translocation?
Breakage of two acrocentric chromosomes at or close to centromeres
With subsequent fusion of their long arms - short arms are lost
What are the acrocentric chromosomes?
13
14
15
21
22
What is Balanced robertsonian translocation?
Still two copies of 14 and 21
All genetic material still present but at different positions
Doesnt affect phenotype
So can be a carrier of robertsonian translocation
1 in 1000 individuals
What is unbalanced robertsonian translocation?
For example two 21 chromosomes and one 14 chromosomes and joined 14+21 chromosome
Down syndrome via robertsonian translocation
What are the possibilities for an offspring of a balances robertsonian carrier? E.g. robertsonian translocation of chromosome 14 and 21
- Normal
- Balanced carrier
- Monosomy 14
- Trisomy 14
- Monosomy 21
- Trisomy 21 Down’s syndrome
What are the lethal chromosomal abnormalities of the offspring of a balanced robertsonian carrier?
- Trisomy 14
- Monosomy 14
- Monosomy 21
Probabilities of recurrence for robertsonian translocation?
- a carrier for robertsonian 14:21 has a high THEORETICAL probability of having Down’s syndrome child
- but in reality, lower probability (male carrier: 1%, female Carrier: 10%)
What is reciprocal translocation?
Breakage of two non homologous chromosomes with exchange of fragments
Can occur btw any non paired chromosomes
Possibilities of offspring for balanced reciprocal translocation carriers?
- Normal
- Balanced carrier
- Partial trisomy + partial Monosomy
- Partial Monosomy + partial trisomy
Risks for a balanced carrier of translocation?
Risk of children having unbalanced translocation
Risks of unbalanced reciprocal translocation carrier?
(Partial trisomy and partial Monosomy)
Miscarriage
Or
Some imbalances compatible with survival depends on which chromosomes
Like congenital malformation, developmental delay, metal abnormality
The size and position of of the chromosome segments in reciprocal translocation may have an effect on:
The pairing of the chromosomes at meiosis
Frequency of diff forms of translocation in the gametes
The likelihood of the conceptus with that abnormality developing to term
Consequences of reciprocal translocation depends on:
Genes on the translocated segments
Amount of chromosome imbalance
Prenatal diagnosis?
testing the fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including certain hereditary or spontaneous genetic disorders.
How do large chromosome deletions and duplications occur?
Due to unequal crossing over in meiosis following mispairing (often at sites of repeated sequences)
Mosaicism?
Two populations of cells with different genetic constitutions usually as a result of an error in mitosis
Chromosome abnormality during mitotic cell division
Somatic mosaicism?
Two populations of cells in body
Gonadal mosaicism?
Two populations of cells only in the gonads
Main points about numerical chromosome abnormalities?
- Gain or loss of complete chromosome
- Common cause is non disjunction
- Serious, often lethal consequences
- Autosomal monosomies are catastrophic
- common numerical abnormalities in live borns trisomy 21,13,18
- fewer serious effects from sex chromosome abnormalities
Is mosaicism for chromosomal anomaly confined to the gonads?
Yes
Main points of structural chromosome abnormalities:
- Translocations involve exchange of material btw two chromosomes
- Robertsonian and Reciprocal
- Individual clinically normal if no loss or gain of genetic material (translocation carrier)
- carrier may cause chromosomal abnormal baby, miscarriage, stillbirth, infertility
- small imbalance: child with multiple congenital abnormalities
- deletions/duplications occur due to recombination btw mispaired chromosomes
What is an inactivated X chromosome called
A Barr body
