L6- Chromosomal Basis of Inheritance Flashcards
What is cytogenetics
Study of chromosomes
What do conventional cytogenetics look at?
- Metaphase chromosome analysis
G-banding
What do Molecular cytogenetics look at?
-Cytogenetic analysis at the molecular resolution at all stages of the cell cycle – DNA or in situ
FISH Microarray CGH Next generation sequencing (NGS) MLPA QF-PCR
At what stage of the cell cycle are chromosomes most visible?
Chromosomes most visible in metaphase in mitosis
Molecular cytogenetics is able to detect at any phase
Stages of Mitosis?
Interphase prophase metaphase anaphase telophase
then cytokinesis
Features/parts of a chromosome?
p arm on top
q arm bottom
telomere part at each end of chromosome
centromere at in the middle
Two types of cytogenetic abnormality
1- structural
2-numerical
How do 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
v. Unmasking of recessive disorder
Numerical chromosome abnormality
Diploidy = 2 copies of each chromosome
- Aneuploidy = gain (trisomy) or loss (monosomy)
- Polyploidy = gain whole sets (triploidy or tetraploidy)
- Mosaicism = diploidy & aneuploidy
Origins of numerical abnormality
- Gametogenesis - meiosis
- Fertilisation
- Early cleavage (post-zygotic non-disjunction)
Learn stages of Meiosis!
Figure it out and learn it!
Meiotic errors- what is Non-disjunction?
- Failure of chromosome or chromatid separation
Clinical features of Trisomy 21 - Down’s Syndrome (Meiotic errors)
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
Trisomy 18 - Edward’s syndrome (Meiotic errors)
-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
-Organ Malformations:
Umbilical or inguinal hernia
Congenital heart disease (90%)
Congenital kidney abnormalities
Eye abnormalities eg. cataracts, micropthalmia
Trisomy 13- Patau’s syndrome (Meiotic errors)
Small at birth
Mental retardation severe
Microcephaly/ sloping forehead
Defects of brain - holoprosencephaly
-Phenotype:
Eyes – microphthalmia, coloboma, retinal dysplasia, palpebral fissures slanted
Cleft lip and/or palate
Ears abnormal and low
Polydactyly & fingers flexed
Heart defect
Abnormal genitalia
Link between Autosomal aneuploidy & maternal age (Meiotic errors)
- Unfavourable chiasmata distribution (foetus)
- Age-dependent deterioration of meiotic structures (10-40y later) - hormonal imbalance, irradiation, oral contraceptives, alcohol, etc
Sex chromosome aneuploidy (Meiotic errors)
no age-related risk
phenotype less severe than autosomal
sexual orientation not affected
Turner’s syndrome (45,X) - 1/2500
Klinefelter’s syndrome (47,XXY) - 1/1000
47,XYY - 1/1000
47,XXX - 1/1000
Features of Turner’s syndrome (Meiotic errors)
45, X
-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
Features of Klinefelter syndrome (Meiotic errors)
47, XXY
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
- Errors at fertilisation
- Polyploidy (usually triploidy)
2. Molar pregnancy (double paternal, no maternal)
Triploidy (Errors at fertilisation)
69,XXY or 69,XYY or 69,XXX
2% all pregnancies
99.9% spontaneously abort
1/57000 livebirths
Origin of triploidy (Errors at fertilisation)
sperm 1N + Egg 2N = Digyny
sperm 2N + Egg N= Diplospermy
2 Sperm Ns + Egg N = Dispermy
Parental origin of triploidy (Errors at fertilisation)
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
Molar pregnancy (Errors at fertilisation)
Consequences:
Double paternal genome
“Conceptus without an embryo”
Massive cystic placenta
- Errors at early cleavage
(mosaicism = mitotic non-disjunction)
Consequences of Mosaicism (Errors at early cleavage)
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”
Summary of numerical abnormality
Numerical abnormalities frequent (genetically unfit)
Gain or loss of single chromosome (meiosis)
Gain of whole chromosome sets (fertilisation)
Gain or loss during mitosis (post-fertilisation)
Chromosome rearrangement - 1) Balanced rearrangements
1) Translocation
- Reciprocal
- Robertsonian
2) Inversion
- Pericentric
- Paracentric
3) Insertion
Reciprocal translocation
Both bits exchange on chromosomes (7 –> 9)
Robertsonian translocation
A whole arm fusion from a chromosome on another
(13–>15)
acrocentrics
1/1000
no phenotype risk
reproductive risk
Inversions (translocation)
two types
1) Pericentric
- inverts on both sides of centromere
2) Paracentric
- Inverts in one of the arms of the chromosomes
Unbalanced rearrangements
Contiguous gene syndromes or genomic disorders
1/2000
Copy number variation (CNV) - Overall net cytogenetic gain &/or loss (from 100s Kb to Mbs)
Commonest = deletions & duplications
Several genes
Mostly sporadic
Deletions (interstitial) (Unbalanced rearrangements)
A segment within the chromosome is lost
Terminal deletion (Unbalanced rearrangements)
A whole segment at the end of chromosome is lost
Duplications (Unbalanced rearrangements)
Gain of segment
gain of two segments can be integrated into chromosome via being directed or inverted
Deletions & duplications
Phenotype - abnormal gene dosage (several genes)
Variable clinical expression – variable size of imbalance, other genetic and environmental effects
Reciprocal duplications – frequency = deletions
Loss > deleterious than excess
Ring chromosome
Breakage at either of chromosome and then circularisation of chromosome (basically looks like a plasmid)
Summary
- Structural rearrangements common
- Balanced - 5-10% risk gene disruption
(phenotype)
- most no phenotypic effect
- reproductive problems - Unbalanced - phenotype
