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L3 Clinical Genomics > PND aneuploidy > Flashcards

PND aneuploidy Flashcards

1
Q

What is aneuploidy?

A

Gain or loss of one or a few chromosomes

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2
Q

What proportion of pregnancies are expected to spontaneously abort? (2)

A
  • Approximately 15%
  • Changes with age (lower for under 30, higher for older)
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3
Q

What are the factors contributing to pregnancy loss? (3)

A
  • Maternal chronic health conditions e.g. diabetes
  • Environmental factors e.g. smoking
  • Inheritance of aneuploidy
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4
Q

What proportion of miscarriages are estimated to be caused by inheritance of an abnormal complement of chromosomes?

A

50%

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5
Q

How does meiosis cause cells to go from diploid to haploid?

A

Single round of DNA replication during interphase followed by 2 rounds of chromosome segregation

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6
Q

What holds sister chromatids together?

A

Sister chromatid cohesion

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7
Q

What is sister chromatid cohesion? (3)

A
  • Cohesin ring structures which hold sister chromatids together
  • Contains Scc1 in mitosis but Rec8 in meiosis
  • Laid down behind replication forks during replication
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8
Q

What is the function of Spo11? (2)?

A
  • 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
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9
Q

What is the synaptonemal complex?

A

Protein complex that holds homologous chromosomes together during prophase of meiosis I

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10
Q

What are the events in prophase I? (4)

A
  • Leptotene
  • Zygotene
  • Pachytene
  • Dictyotene
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11
Q

How does homologous recombination occur within the synaptonemal complex? (4)

A
  • 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
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12
Q

What is the first repair pathway within the synaptonemal complex? (2)

A
  • 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
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13
Q

What is the other repair pathway within the synaptonemal complex? (4)

A
  • 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
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14
Q

What is disjunction?

A

Faithful chromosome segregation

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15
Q

What are chiasmata?

A

Structures formed by crossing over events

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16
Q

What happens at the end of meiosis I? (2)

A
  • 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
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17
Q

What is faithful segregation of chromosomes in MII dependent on? (2)

A
  • Sister chromatid cohesion remains intact after MI
  • The appropriate number and positioning of crossovers must occur in MI for MII to happen normally
18
Q

What are the major examples of viable human aneuploidies? (4)

A
  • Trisomy 21 (Down syndrome)
  • Trisomy 18 (Edwards’ syndrome)
  • Trisomy 13 (Patau syndrome)
  • Sex chromosome aneuploidies
19
Q

What is the cause of Down syndrome? (2)

A
  • Gain of a critical region on 21q
  • Trisomy is the cause for more than 95% of cases but isn’t the only cause
20
Q

What are the features of Down syndrome? (4)

A
  • 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
21
Q

Why is trisomy 21 largely viable?

A

21 is the smallest chromosome which is likely to be a major factor

22
Q

What are the effects of trisomy 18? (2)

A
  • 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
23
Q

What are the effects of trisomy 13? (2)

A
  • 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
24
Q

Why does sex chromosome aneuploidy results in live birth? (2)

A
  • Gene poor nature of the Y chromosome
  • X chromosome inactivation
25
Q

What is the only viable human monosomy? (3)

A
  • Sex chromosome monosomy seen in Turner syndrome (45, X)
  • Present in 1 in 2000 live births
  • Autosomal monosomy is lethal in humans
26
Q

What are examples of tolerated genomic imbalance of the sex chromosomes? (3)

A
  • Klinefelter syndrome (47, XXY) (disomy)
  • Triple X syndrome (47, XXX) (trisomy)
  • Associated with low levels of spontaneous abortion
27
Q

Why are pregnant women offered screening between 10 and 14 weeks gestation?

A

To test for common aneuploidies (21, 18, 13, X and Y) which result in around 30% of miscarriages

28
Q

What is the screening programme for common aneuploidies? (2)

A
  • 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
29
Q

Which hormones are measured in the blood test of the combined test? (2)

A
  • Pregnancy associated plasma protein A (PAPP-A)
  • Free B-human chorionic gonadotropin
30
Q

What is a positive screening result for the combined test? (2)

A
  • A risk of 1 in 150
  • Further investigations include genetic screen (could be free foetal DNA qPCR, FISH, karyotyping)
31
Q

What are morphological markers of genetic abnormalities that can be picked up in routine ultrasound scans? (5)

A
  • 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
32
Q

What is a major risk factor for aneuploidy? (2)

A
  • Advanced maternal age
  • Around 2% of pregnancies are trisomic for woman under 25, increases to 30% for women over 40
33
Q

How do you identify the origin of chromosomal imbalance for aneuploid pregnancies?

A

Characterise highly polymorphic regions of the genome on the affected chromosome and compare the identity with parental homologs

34
Q

What is usually the origin of the extra 21 in Down syndrome?

A

Maternal

35
Q

How do you identify at which point in meiosis the error occured?

A

Look at polymorphic regions close to the centromere where a crossover is unlikely to have occurred so allelic identity is preserved

36
Q

What is the importance of the number of crossovers in aneuploidy formation? (2)

A
  • 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
37
Q

What is the importance of the position of the crossover in the formation of aneuploidy? (6)

A
  • 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
38
Q

Why is advanced maternal age associated with aneuploidy? (4)

A
  • 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
39
Q

What features can an abnormal bivalent have? (3)

A
  • 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
40
Q

What is the 2 hit model for age-dependent aneuploidy? (3)

A
  • 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

L3 Clinical Genomics (14 decks)

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