Lecture 6 GiM Flashcards
What is cytogenetic?
Study of chromosome
Anything more than a single gene
How many pairs of chromosome are there in a nucleus?
23
What is chromosome 1-22 called?
Autosomes
List the different types of cytogenetic analysis
Conventional cytogenetics
- G-band metaphase chromosome analysis
Molecular cytogenetics
-FISH
-microarray chromosomal genomic hybridisation
-Next generation sequencing
-Multiplex ligation-dependent probe amplification (MLPA)
-QF-PCR
qPCR
How many genes and bands are there in a karyotype sample?
30000 genes
550 bands
What are the terminal part of a chromosome called?
Telomere
How do cytogenetic abnormalities produce an abnormal phenotype?
- Dosage effect
- Disruption of a gene
- Effect due to parental origin
- Position effect
- Unmasking of recessive disorder
Which are more deleterious, gain or loss of genes?
Loss are more deleterious than excess
What can disrupt genes in a chromosome?
breakpoint and inappropriate activation/inactivation
What is breakpoints?
breakpoints in the genome are locations on a chromosome where DNA might get deleted, inverted, or swapped around.
What is genomic imprinting?
Genomic imprinting is the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed. If the allele from the mother is imprinted, then only the allele from the father is expressed
What are the two types of cytogenetic abnormalities?
Structural and numerical
If a baby survive from a cytogenetic abnormalities, what might be the potential phenotypic imbalances experienced by her?
- Facial dysmorphism
- organ malformation
- compromised mental/intelectual functioning
What are the three different types of numerical chromosome abnormality?
- Aneuploidy = gain (trisomy) or loss (monosomy)
- Polyploidy = gain whole sets (triploidy or tetraploidy)
- Mosaicism = diploidy & aneuploidy
What are the origins/causes of numerical chromosome abnormality?
- Aneuploidy - Gametogenesis/meiosis
- Polyploidy - Fertilisation
- Mosaicism - Post-zygotic non-disjunction (Early cleavage)
What is the factor that increase the susceptibility to aneuploidy?
Increase maternal age
During the meiotic error, what is the probability that the error happens in meiosis I rather than meiosis II ?
80% - 90%
What are the examples of autosomal aneuploidy
Trisomy 18 (Edwards syndrome) Trisomy 13 (Patau syndrome) Trisomy 21 (Down syndrome)
All aneuploidies are possible, why only three chromosomes involved?
s
What are the epidemiology of trisomy 21?
1/700
75% spontaneously abort
What are the characteristics of a baby with trisomy 21?
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 characteristics of an adult with trisomy 21?
Fertility Females – normal, males usually infertile Average life 55-68y Medical problems -increase risk (mainly leukaemia) cancer -Alzheimer’s -Hypothyroid -Obesity/coeliac, arthritis, diabetes, hearing loss, seizures
What do you know about Edwards syndrome?
Trisomy 18
~ 1 in 6000 livebirths (95% spontaneously abort)
10% survive >1y
What are the clinical pictures of someone with Edwards syndrome?
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 examples of organs malformations happened in Edwards syndrome?
Umbilical or inguinal hernia
Congenital heart disease (90%)
Congenital kidney disease
Eye abnormalities eg: cataracts, micropthalmia
What is micropthalmia?
In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present
What is patau syndrome?
Trisomy 13
~ 1/12 000 livebirths (95% spont ab)
Small at birth
Mental retardation severe
Microcephaly/ sloping forehead
Defects of brain - holoprosencephaly
What is holoprosencephaly?
Holoprosencephaly (HPE, once known as arhinencephaly) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.
The condition can be mild or severe. According to the National Institute of Neurological Disorders and Stroke (NINDS), “in most cases of holoprosencephaly, the malformations are so severe that babies die before birth.”[1]
When the embryo’s forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.
In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip.
What are the phenotypes of someone with trisomy 13 (Patau syndromes)?
Eyes – microphthalmia, coloboma, retinal dysplasia, palpebral fissures slanted
Cleft lip and/or palate
Ears abnormal and low
Polydactyly & fingers flexed
Heart defect
Abnormal genitalia
What are the maternal age factors that lead to autosomal aneuploidy?
- Unfavourable chiasmata distribution (foetus)
- Age-dependent deterioration of meiotic structures (10-40y later) - hormonal imbalance, irradiation, oral contraceptives, alcohol, etc
What are the characteristics of sex chromosome aneuploidy?
- No age related risk
- Phenotype less severe than autosomal
- Sexual orientation not affected
What is Turner’s syndrome?
(45,X) - 1/2500
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 sibsWhat is Klinefelter Syndrome?
(47,XXY) - 1/1000
How can diagnosis someone with Klinefelter syndrome?
Most undiagnosed (~64%) Identified through infertility &/or hypogonadism
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 error that may happen during fertilisation?
- Polyploidy (usually triploidy)
2. Molar pregnancy (double paternal, no maternal)
What are the characteristics of someone with triploidy?
69,XXY or 69,XYY or 69,XXX
2% all pregnancies
99.9% spontaneously abort
1/57000 livebirths
What is digyny?
1 sperm (n) + 1 ovum (2n)
What is diplospermy?
1 sperm (2n) + 1 ovum (n)
What is dispermy ?
2 sperm + 1 ovum
What are 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 mosaicism?
A mosaic or mosaicism denotes the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg.
What is the consequences of mosaicism?
Variable phenotype
Variable lethality foetal vs extraembryonic
Non-identical twin
Tissue-specificity – lateral asymmetry
May generate Uniparental disomy (UPD)
Recurrence risk (if gonadal)
“All females are mosaic”
What is reciprocal translation?
Reciprocal translocations are usually an exchange of material between nonhomologous chromosomes. Estimates of incidence range from about 1 in 500 to 1 in 625 human newborns. Such translocations are usually harmless and may be found through prenatal diagnosis.
What is robertsonian translocation?
Robertsonian translocation (ROB) is a rare form of chromosomal rearrangement that in humans occurs in the five acrocentric chromosome pairs, namely 13, 14, 15, 21, and 22.
Whole arm fusion
What is paracentric inversion?
Paracentric inversions do not include the centromere and both breaks occur in one arm of the chromosome
What is pericentric inversion?
An inversion in which the breakpoints occur on both arms of a chromosome.
What is copy number variation(CNV)?
A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next. Following the completion of the Human Genome Project, it became apparent that the genome experiences gains and losses of genetic material.
What is the commonest unbalanced rearrangements?
Deletions and duplications
What is acrocentric chromosome?
A chromosome in which the centromere is located quite near one end of the chromosome. Humans normally have five pairs of acrocentric chromosomes.
