Lecture 4.1: Chromosomal Abnormalities Flashcards
What is a karyotype?
It is the actual picture of an individual’s collection of chromosomes
Is a preparation of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, sorted by length, centromere location and other features
22 pairs of autosome chromosomes and 1 pair of sex chromosomes
Karyotypes
Describe the number of chromosomes and what they look like (size bands and centromere placement)
Karyograms
Are the study of the whole set of chromosomes arranged in pairs by size, and position of the centromere
Chromosome Ideogram
Is a graphical or schematic representation of chromosomes
Each arm of the chromosome is divided into regions, and the numbers assigned to each region get larger as the distance from the centromere to the telomere increases
Regions are identified by the specific morphological features that are consistently found in a chromosome, such as the presence of prominent Giemsa-staining bands
What is Karyotyping?
It is the process of pairing and ordering all the chromosomes of an individual
Why do we do Karyotyping?
To detect changes in chromosome number and also more subtle structural changes, such as chromosomal deletions, duplications, translocations, or inversions
How do we do Karyotyping?
Prepared from mitotic cells that have been arrested in metaphase or prometaphase, when chromosomes are most condensed
What tissues are used for Karyotyping?
A variety of tissue types can be used as a source of these cells: peripheral blood, skin biopsy, tumour biopsies or bone marrow samples
In embryos: amniotic fluid or chorionic villus specimens are used
Normal Chromosome Report: What to expect?
46, XX- normal female karyotype
46, XY- normal male karyotype
Indications for carrying out Karyotyping (5)
1) Prenatal screening
2) Birth defects
3) Abnormal sexual development
4) Infertility; Recurrent foetal loss
5) Leukaemia and related disorders
Chromosomal Abnormalities
1) Polyploidy
2) Aneuploidy
3) Chromosomal mutations: Deletion, Inversion, Translocation, Insertion,
Duplication
What is Polyploidy?
It is the heritable condition of possessing more than two complete sets of chromosomes
Polyploidy can occur in some tissues of animals that are otherwise diploid – endoploidy (human muscle tissues)
Polyploidy in Humans
It is lethal
Polyploidy occurs in humans in the form of triploidy, with 69 chromosomes (sometimes called 69,XXX)
Tetraploidy with 92 chromosomes (sometimes called 92,XXXX)
Triploidy is often caused by polyspermy
What is Aneuploidy?
Is the presence of an abnormal number of chromosomes in a cell
Aneuploidy is the most common and clinically significant type of human chromosome abnormality
Trisomies
In humans, the most common aneuploidies are trisomies, which represent about 0.3% of all live births
Trisomies represent about 35% of spontaneous abortions
What causes Aneuploidy?
The most common cause of aneuploidy is the nondisjunction of chromosomes during meiosis
The vast majority of trisomies arise from errors during maternal meiosis I (human oocytes can be arrested in prophase I for several decades)
Autosome Aneuploidies Conditions
Trisomy 21: Down’s Syndrome (viable)
Trisomy 18: Edwards’s Syndrome
Trisomy 13: Patau Syndrome
Why is Trisomy 21 viable?
Likely because the number of protein-coding sequences for chromosome 21 is the smallest of any human chromosome (except Y)
Thus, an additional copy of chromosome 21 would be predicted to perturb the normal equilibrium in cells less than an extra copy of any other autosome
Down syndrome: Three variations
47,XY(or XX),+21
Trisomy 21
Mosaic Down Syndrome: person has only some cells with an extra copy of
chromosome 21
Translocation Down Syndrome: a portion of chromosome 21 becomes attached (translocated) onto another chromosome, before or at conception
Down syndrome: Distinct Features
- Flattened face
- Small head
- Short neck
- Protruding tongue
- Upward slanting eye lids (palpebral fissures)
- Unusually shaped or small ears
- Poor muscle tone
- Broad, short hands with a single crease in the palm
- Relatively short fingers and small hands and feet
- Excessive flexibility
- Tiny white spots on the coloured part (iris) of the eye called Brushfield’s spots
- Short height
Down syndrome: Symptoms
- Mild to moderate intellectual disability (IQ 35–70)
- Congenital heart disease
- Haematological malignancies are more common in children with DS (acute
lymphoblastic leukaemia (ALL) 10x higher) - Hypothyroidism
- Gastrointestinal: lack of nerves in colon (constipation)
- Reduced fertility
- Eye disorders: strabismus, refractive errors, cataracts
- Hearing disorders: seen in 38–78% of DS children mostly due to infections
and malformations (can be treated)
Down syndrome: Diagnostic Methods
1) G-banded karyotype
2) Fluorescent in situ hybridization (FISH)
3) Quantitative fluorescence PCR (QF-PCR)
Edwards Syndrome
47,XX(or XY),+18
Occurs in around 1 in 6000 live births ( ~80% of affected individuals are female)
Modal lifespan is 5–15 days
5-10% of infants survive longer than 1 year
Edwards Syndrome: Symptoms
- Slow growth before birth (intrauterine growth retardation) and a low birth
weight - May have heart defects and abnormalities of other organs that develop
before birth - Issues with cognitive development (intellectual disabilities), which are
typically severe. - Weak cry and minimal response to sound
Edwards Syndrome: Distinct Features
- Unusually small head
- Back of head is prominent
- Ears malformed + low set
- Mouth and jaw are small (may have cleft lip/palate)
- Hands are clenched into fists and index overlaps other fingers
- Clubfeet and toes may be fused/ webbed
Patau Syndrome
47,XY(or XX) ,+13
5 – 10% of children with this condition live past their first year
Small percentage reach early adulthood
Patau Syndrome: Symptoms
- Severe intellectual disability
- Congenital heart defects
- Brain or spinal cord abnormalities
- Very small or poorly developed eyes (microphthalmia)
- Low-set ears
- Extra fingers and/or toes (polydactyly)
- Cleft lip or palate
- Decreased muscle tone (hypotonia)
Patau Syndrome: Distinct Features
- Small head
- Absent eyebrows
- Cleft lip/palate
- Dysplastic/ malformed ears
- Clenched hands
- Polydactyly
- Undescended/ abnormal testes
Sex Chromosome Aneuploidies
Humans are much more able to tolerate extra sex chromosomes than extra autosomes
This tolerance most likely relatesto both X inactivation and to the small number of genes on the Y chromosome
Sex Chromosome Aneuploidies: Conditions
Turner syndrome: 45,X
Triple X syndrome: 47,XXX
Klinefelter syndrome: 47,XXY
XYY syndrome: 47,XYY
X Chromosome Inactivation
By transcriptional silencing occurs randomly for one of the two X chromosomes in female cells during development
Each female is a mosaic of cells in which either the maternally inherited or the paternally inherited X is silenced
X chromosome inactivation equalizes dosage of gene products from the X
chromosome between XX females and XY males
Turner Syndrome
45,X or 45, X0
Is the most common sex chromosome abnormality in females
5 – 10% of children with this condition live past their first year
Multiple congenital abnormalities
Turner Syndrome: Symptoms
- Short stature
- Retarded sexual development
- Cardiovascular problems (bicuspid aortic valve, coarctation of the aorta,
elongation of the aortic arch, hypertension) - Kidney defects occur in 30% to 40% of people with TS
- Hearing and ear problems (hearing loss develops in more
than 50% of adults with TS) - No mental retardation
Why is a single X a problem?
Because NOT all genes on the inactivated X chromosome are transcriptionally silenced (15-20%)
PAR1 and PAR2 (PseudoAutosomal Regions) are short regions of homology between the mammalian X and Y chromosomes (act as autosomes during A1)
All characterised genes within PAR1 escape X chromosome inactivation → Turner syndrome patients will be monosomic for genes in the PARs
Triple X Syndrome
47,XXX
Two of the three X chromosomes are inactivated leaving one active
Being taller than average height is the most typical physical feature
Triple X Syndrome: Symptoms
Symptoms vary, many experience no noticeable effects or have only mild symptoms
Occasionally:
- Delayed development of speech and language skills
- Learning disabilities
- Behavioural problems
- Psychological problems
- Problems with fine and gross motor skills, memory, judgment
and information processing
Klinefelter Syndrome
47, XXY
Symptoms appear after the onset of puberty
Treatment: sex hormones and surgery
Klinefelter Syndrome: Symptoms/ Characteristics
- Taller
- Less muscular body than males their age
- Gynecomastia (increased breast tissue)
- Poor beard/ chest hair growth
- Narrow shoulders
- Wider hips
- Small testicular size
XYY Syndrome
47,XYY
Not really a syndrome, since the phenotype is essentially normal
Increased growth rate from early childhood - 7 cm taller than average
Normal testosterone levels, fertility and intelligence (IQ can be 10-15 less than siblings)
Chromosomal Translocation
The breakpoints on the two chromosomes often lie between genes
a person with this translocation will have the full complement of genes: no phenotype
BUT… Offspring could be unbalanced and will probably have a phenotype
Robertsonian Translocation
Results from breakage of two acrocentric chromosomes (13, 14, 15, 21, 22) at or close to their centromeres & the long arms fuse to form one chromosome
The total chromosome number in a Robertsonian translocation carrier is therefore reduced to 45
No gain or loss of important genetic material occurs, no phenotype
Effect of Robertsonian Translocation on offspring
Robertsonian translocation carriers are asymptomatic but often produce
unbalanced gametes during meiosis
This can result in monosomic or trisomic zygotes
Philadelphia Chromosome: what is it? how? treatment?
Results from a reciprocal translocation between chromosomes 9 and 22
This translocation creates a fusion gene: BCR-ABL encoding for a fusion protein BCR-ABL that is oncogenic
Therapy: BCR-ABL tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with (CML)
How to abbreviate chromosomes/ genes on chromosmes
Chromosome is put first
The shorter arm is called p
The longer arm is called q
E.g. 17p12: chromosome 17 short arm at position 12
What does 19q14 mean?
Chromosome 19
Long arm
Position 14
Interstitial and Terminal Deletions
Regions of chromosomes can become deleted interstitially or terminally by breakage
Such deletions will always be unbalanced and normally there will be an associated phenotype
Deletions might be large enough to be visible by standard light microscopy otherwise FISH
