PND aneuploidy Flashcards
What is aneuploidy?
Gain or loss of one or a few chromosomes
What proportion of pregnancies are expected to spontaneously abort? (2)
- Approximately 15%
- Changes with age (lower for under 30, higher for older)
What are the factors contributing to pregnancy loss? (3)
- Maternal chronic health conditions e.g. diabetes
- Environmental factors e.g. smoking
- Inheritance of aneuploidy
What proportion of miscarriages are estimated to be caused by inheritance of an abnormal complement of chromosomes?
50%
How does meiosis cause cells to go from diploid to haploid?
Single round of DNA replication during interphase followed by 2 rounds of chromosome segregation
What holds sister chromatids together?
Sister chromatid cohesion
What is sister chromatid cohesion? (3)
- Cohesin ring structures which hold sister chromatids together
- Contains Scc1 in mitosis but Rec8 in meiosis
- Laid down behind replication forks during replication
What is the function of Spo11? (2)?
- Topoisomerase which is recruited during replication
- Makes double strand breaks in DNA which stimulates pairing of homologous chromosomes and the formation of the synaptonemal complex
What is the synaptonemal complex?
Protein complex that holds homologous chromosomes together during prophase of meiosis I
What are the events in prophase I? (4)
- Leptotene
- Zygotene
- Pachytene
- Dictyotene
How does homologous recombination occur within the synaptonemal complex? (4)
- Spo11 causes double strand breaks which initiates DNA end resection to form single strands that can invade a nearby duplex with homologous sequence
- Synaptonemal complex encourages single strand invasion of the homologous duplex
- The strand invasion intermediate needs to be processed to repair the break
- The repair pathway splits into two streams
What is the first repair pathway within the synaptonemal complex? (2)
- Resolves the repair intermediate in a way that untangles the homologous chromosomes
- Results in sister chromatid cohesion linking the paternal sister chromatids together and the maternal sister chromatids together separately
What is the other repair pathway within the synaptonemal complex? (4)
- Repairs the break by covalently linking the broken chromatid to the invaded chromatid of the homolog, creating a crossover
- Sister chromatid cohesion from both homologs now holds the 2 homologous chromosomes together
- This mechanism physically links the homologous chromosomes in meiosis
- Crossing over is essential for faithful segregation and introduces genetic diversity
What is disjunction?
Faithful chromosome segregation
What are chiasmata?
Structures formed by crossing over events
What happens at the end of meiosis I? (2)
- Bivalents are aligned on the metaphase plate and homologous chromosomes are pulled to opposite poles of the cell by the mitotic spindle
- Separase enzyme destroys Rec8 which is a key component of the cohesion complex to allow the chiasmata to resolve, untangling and segregation
What is faithful segregation of chromosomes in MII dependent on? (2)
- Sister chromatid cohesion remains intact after MI
- The appropriate number and positioning of crossovers must occur in MI for MII to happen normally
What are the major examples of viable human aneuploidies? (4)
- Trisomy 21 (Down syndrome)
- Trisomy 18 (Edwards’ syndrome)
- Trisomy 13 (Patau syndrome)
- Sex chromosome aneuploidies
What is the cause of Down syndrome? (2)
- Gain of a critical region on 21q
- Trisomy is the cause for more than 95% of cases but isn’t the only cause
What are the features of Down syndrome? (4)
- Detected in 1 in 700 births
- Intellectual and developmental problems that range in severity (influenced by the types of tissue affected and level of mosaicism)
- Physical morphological changes and physiological risks (heart defects, increased risk of dementia etc.)
- Predisposition to a particular acute myeloid leukaemia
Why is trisomy 21 largely viable?
21 is the smallest chromosome which is likely to be a major factor
What are the effects of trisomy 18? (2)
- 95% of pregnancies with trisomy 18 spontaneously abort
- Those that come to term have Edwards’ syndrome and are expected to survive for approx 24 hours
What are the effects of trisomy 13? (2)
- 99% of pregnancies with trisomy 13 are expected to spontaneously abort
- Those that come to term have Patau syndrome and are expected to live for a few days
Why does sex chromosome aneuploidy results in live birth? (2)
- Gene poor nature of the Y chromosome
- X chromosome inactivation
What is the only viable human monosomy? (3)
- Sex chromosome monosomy seen in Turner syndrome (45, X)
- Present in 1 in 2000 live births
- Autosomal monosomy is lethal in humans
What are examples of tolerated genomic imbalance of the sex chromosomes? (3)
- Klinefelter syndrome (47, XXY) (disomy)
- Triple X syndrome (47, XXX) (trisomy)
- Associated with low levels of spontaneous abortion
Why are pregnant women offered screening between 10 and 14 weeks gestation?
To test for common aneuploidies (21, 18, 13, X and Y) which result in around 30% of miscarriages
What is the screening programme for common aneuploidies? (2)
- The combined test which generates a numerical risk for pregnancy being affected by a common aneuploidy
- Based on nuchal translucency diameter and a blood test which measures levels of 2 hormones
Which hormones are measured in the blood test of the combined test? (2)
- Pregnancy associated plasma protein A (PAPP-A)
- Free B-human chorionic gonadotropin
What is a positive screening result for the combined test? (2)
- A risk of 1 in 150
- Further investigations include genetic screen (could be free foetal DNA qPCR, FISH, karyotyping)
What are morphological markers of genetic abnormalities that can be picked up in routine ultrasound scans? (5)
- Abnormal cardiac activity
- Abnormal kidney and bowel features
- Characteristic clenched fist (1st and 4th fingers overlapping the middle 2 fingers) and rocker bottom feet: trisomy 18
- Cyclopia and polydactyly: trisomy 13
- Short thigh, arm and nose bones: Down syndrome
What is a major risk factor for aneuploidy? (2)
- Advanced maternal age
- Around 2% of pregnancies are trisomic for woman under 25, increases to 30% for women over 40
How do you identify the origin of chromosomal imbalance for aneuploid pregnancies?
Characterise highly polymorphic regions of the genome on the affected chromosome and compare the identity with parental homologs
What is usually the origin of the extra 21 in Down syndrome?
Maternal
How do you identify at which point in meiosis the error occured?
Look at polymorphic regions close to the centromere where a crossover is unlikely to have occurred so allelic identity is preserved
What is the importance of the number of crossovers in aneuploidy formation? (2)
- Reduction in the number of crossovers between homologous chromosomes in MI is a likely cause of aneuploidy because crossovers are needed to hold homologous chromosomes together
- Too many MI crossovers is linked to MII non-disjunction errors
What is the importance of the position of the crossover in the formation of aneuploidy? (6)
- Too close to the telomere = more likely to mal-segregate during MI
- Too close to the centromere = errors more likely in MII
- Crossover connects the homologs because the sister chromatid cohesion connects the original chromatid to the homologous chromatid
- This allows the mitotic spindle to exert tension across the bivalent
- No crossovers = homologous chromosomes can move independently of each other so 50% chance of both segregating to the same pole
- Single distal crossover reduces the amount of sister chromatid cohesion so can’t balance the mitotic spindle force = predisposed to MI non-disjunction
Why is advanced maternal age associated with aneuploidy? (4)
- Meiotic process begin during foetal development in females and oocytes enter a period of extended arrest just before birth
- Chromosomes are held together in bivalents during arrest which is dependent on chiasmata and sister chromatid cohesion
- These structures become damaged during arrest which leads to mal-segregation events
- More crossovers present = more likely to maintain stability in the event of damage
What features can an abnormal bivalent have? (3)
- Only 1 crossover holding the chromosomes together when it would normally be more than 1
- The single crossover being abnormally positioned (i.e. too close to telomere/centromere)
- Too many crossovers can also be abnormal
What is the 2 hit model for age-dependent aneuploidy? (3)
- Establishment of a susceptible abnormal bivalent
- Abnormal processing of the susceptible bivalent during meiosis I i.e. during the prolonged meiotic arrest
- Therefore the longer the arrest, the older the individual and the greater chance of mal-segregation
