Cytogenetic basis of disease Flashcards
What techniques are used in conventional cytogenetics?
G banding
What techniques are used in molecular cytogenetics?
FISH
Microarray CGH
Next generation sequencing (NGS)
MLPA
QF-PCR
qPCR
What is the advantage of molecular cytogenetics over conventional?
Molecular can be used at any stage of the cell cycle.
How to cytogenetic abnormalities produce an abnormal phenotype?
Dosage effect (gain or loss)
- Loss > deleterious than excess
Disruption of a gene
- Breakpoint
- Inappropriate activation/inactivation
Effect due to the parental origin
- Genomic imprinting
Position effect
- A gene in a new chromosomal environment functions inappropriately
Unmasking of recessive disorder
What are the possible origins of numerical abnormality?
- Gametogenesis - meiosis
- Fertilisation
- Early cleavage (post-zygotic non-disjunction)
What are the risk factors for errors at gametogenesis?
Increased maternal age = increased risk of aneuploidy
Is meiotic non-disjunction more likely to occur at meiosis I or II?
80-90% occurs at meiosis I
What is the other name given to trisomy 18?
Edward’s syndrome
What is the name given to trisomy 13
Patau’s syndrome
Why are trisomies 21, 18 and 13 the only autosomal polyploidies we see in life?
They are relatively small chromosomes with fewer genes.
What are the clinical features of trisomy 21?
1/700 live births
75% spontaneously abort
Head
- Eyes: upward slanting; brushfield spots
- Nose: Small
- Ears: abnormally shaped/low set
- Tongue: protruding
- General – flat face, brachycephalic, short neck
Neurological
- Learning disabilities (mild to moderate IQ 30-60)
Hands and feet
- single palmar crease
- short broad hands
- 5th finger clinodactyly
- wide gap (sandal gap) between the 1st & 2nd toes
What are the particular features of trisomy 21 in adults?
Fertility
- Females – normal, males usually infertile
- *Average life 55-68y**
- *Medical problems**
- risk (mainly leukaemia) cancer
- Alzheimer’s
- Hypothyroid
- Obesity/coeliac, arthritis, diabetes, hearing loss, seizures
What are the clinical features of Edward’s syndrome?
1 in 6000 livebirths (95% spontaneously abort)
10% survive >1y
Head: microcephaly; low set ears; micrognathia; ears low set; cleft lip and palate
Hands & feet: Clenched hands, overlapping fingers; Rockerbottom feet
Low birth weight
Short sternum
Severe mental retardation
What are the clinical features of patau syndrome?
1/12 000 livebirths (95% spont ab)
Small at birth
Mental retardation severe
Microcephaly/ sloping forehead
Defects of brain - holoprosencephaly
Eyes – microphthalmia, coloboma, retinal dysplasia, palpebral fissures slanted
Cleft lip and/or palate
Ears abnormal and low
Polydactyly & fingers flexed
Heart defect
Abnormal genitalia
Is there an age-related risk associated with sex chromosome aneuploidy?
No
What are the features of Turner’s syndrome?
Reproductive
- Loss of ovarian function
- No puberty
- Infertility
Lymphatic (obstruction)
- Webbed neck
- Swelling of hands &/or feet
Others
- Skeletal Abnormalities – short stature
- Coarctation of aorta
- IQ generally normal/reduced compared to sibs
What are the features of Klinefelter syndrome?
Diagnosis:
- Most undiagnosed (~64%)
- Identified through infertility &/or hypogonadism
Cytogenetics:
- 80% 47,XXY; 20% mosaic or variant
Infertility
- May lack secondary sexual characteristics
- Testicular dysgenesis
- 30-50% gynaecomastia (20x risk breast cancer)
Growth
- Normal in infants, then accelerates
- Adults long legs and arms
IQ normal
- Family background IQ important
- IQ may decrease with increased Xs
What are the possible origins of triploidy?
Digyny, diplospermy (one diploid sperm) and dispermy
What is the significance of the parental origin of triploidy?
•Double paternal = large placenta
= some growth delay
• Double maternal = tiny placenta
= significant growth delay
= head-saving macrocephaly
Conclusions: Maternal genome for foetus
Paternal genome for placenta
What is a molar pregnancy?
On haploid sperm fuses with an empty egg. Result is a massive cystic placenta = ‘conceptus without an embryo’
Where does mosiacism occur?
An error at early cleavage - mitotic non-disjunction.
What are the potential balanced chromosomal rearrangements that may occur?
1.Translocation
- Reciprocal
- Robersonian
2.Inversion
- Pericentric
- Paracentric
3.Insertion
What is a reciprocal translocation?
An exchange of material between nonhomologous chromosomes. They swap reciprocal segments of the chromosome and the result is two altered chromosomes with the same genes carried between them.
What is a Robertsonian translocation?
Fusion of the long arms of two acrocentric chromosomes. The short arms are usually lost. Heterozygotes are balanced carriers; homozygotes are trisomies.
What is a chromosomal inversion?
An inversion is achromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occurs when a single chromosomeundergoes breakage and rearrangement within itself. Inversions are of two types: paracentric and pericentric.
What is the difference between paracentric and pericentric inversions?
Paracentric inversions do not include the centromere and both breaks occur in one arm of the chromosome. Pericentric inversions include the centromere and there is a break point in each arm.
What is an interstitial deletion?
A segment of chromosome not involving the telomere is lost.
What is a terminal deletion?
A segment including the telomere is lost.
What is duplication?
Gain of a segment - may be direct or inverted.
