20.05.12 Cytogenetics of miscarriage & techniques for investigation

Question 1

What percentage of liveborns have an unbalanced chromosomal abnormality

Answer 1

<1%

Question 2

Percentage of oocytes and sperm with chromosomal abnormalities

Answer 2

• Oocytes= 20-25%

- Sperm= 10%

Question 3

Difference between a still birth and a miscarriage

Answer 3

• the spontaneous end of a pregnancy at a stage where the embryo/fetus is incapable of surviving independently (miscarriage) prior to 24 weeks
• Pregnancy loss where a baby can potentially have been born and survived (>24 weeks)= still birth.

Question 4

What proportion of pregnancies are lost in first trimester

Answer 4

• 10-15%

- Single trisomy accounts for ~60% cases

Question 5

What are the most common trisomies in liveborns and associated with advanced maternal age

Answer 5

• Trisomy 13 (Pataumsyndrome)
• Trisomy 18 (Edwards syndrome)
• Trisomy 21 (Down syndrome)

Question 6

Common cause of trisomy

Answer 6

Maternal meiosis I non-disjunction (exceptions= Trisomy 18 and 15)

Question 7

How does trisomy 18 commonly arise

Answer 7

Error at maternal meiosis II

Question 8

How does trisomy 15 commonly arise

Answer 8

Meiosis 1 and II non-disjunction

Question 9

Why is aneuploidy significantly associated with maternal age

Answer 9

Reduced recombination, spindle errors, reduced immunological competence of an older mother.

Question 10

What proportion of pregnancies are lost in second trimester

Answer 10

• 2-5%

- Chromosomal abnormalities in ~50%. Higher proportion of structural rearrangements reported

Question 11

What proportion of pregnancies are lost in third trimester

Answer 11

• 0.5%

- Small proportion due to a chromosomal abnormality (5%)

Question 12

Chromosomal abnormalities that nearly always cause pregnancy loss

Answer 12

• Trisomy 16 (unless mosaic)
• Haploidy (n)
• Triploids (3n)
• Tertraploids (4n)
• 45,X (95%). Hypothesised that Turner syndrome patients are mosaic (or were early in development)

Question 13

In triploidy, what do diandry and digyny mean

Answer 13

• Diandry= two paternal chromosome sets (due to dispermy)

- Digyny= two maternal chromosome sets (diploid egg)

Question 14

What are the two types of uniparental diploidy

Answer 14

• Diandric diploidy (complete mole)= two sperm enter empty ovum. No embryo
• Dygynic diploidy (ovarian teratoma)= 46 chromosomes from mother. Fatal

Question 15

What proportion o miscarriages have unbalanced rearrangements

Answer 15

1-2%

Question 16

Other causes of miscarriage

Answer 16

• Confined placental mosaicism

- Cytogenetic abnormality present only in the placenta, causing it to grow incorrectly.

Question 17

Proportion of women with recurrent miscarriage

Answer 17

1%

Question 18

The Royal College of Obstetricians and Gynaecologists define recurrent miscarriage as:

Answer 18

3 or more miscarriages before 24 weeks post-menstruation

Question 19

Causes of recurrent miscarriage

Answer 19

• Epidemiological factors
• Parental and/or embryonic genetic abnormalities
• Anatomic/structural abnormalities (uterus, cervical weakness)
• Maternal endocrine and immune response anomalies (anti-phospholipid syndrome, thyroid dysfunction)
• Infective agents
• Acquired thrombophilic defects
• Unexplained

Question 20

What proportion of recurrent miscarriage couples carries a balanced structural chromosome rearrangement

Answer 20

2-5% (commonly balanced reciprocal or Robertsonian translocations)

Question 21

What referrals are accepted for testing in pregnancy loss

Answer 21

• Pregnancy loss/termination with significant fetal malformation (irrespective of gestation)
• Pregnancy loss >24 weeks
• Miscarriages <24 weeks, for 3rd and subsequent consecutive miscarriage(s)

Question 22

When should parental samples be karyotyped

Answer 22

When an unbalanced chromosomal abnormality is detected in product of conception.

Question 23

Why have the ACC Solid tissue Best practice guidelines (2010) stated that molecular based techniques can be used instead of karyotyping products of conception (POC)

Answer 23

-Reliance on cell culture of POCs can cause issues:

• Maternal cell contamination (requires careful selection and dissection)
• Higher risk of infection
• Culture failure common due to lack of viable fetal cells
• Mosaicism may be present due to biological (vanishing twin, chimerism, CPM, true constitutional mosaicism) or technical (culture artefact, maternal contamination) reasons

Question 24

Current tests available for investigating recurrent pregnancy loss

Answer 24

• QF_PCR: look for whole chromosome loss/gain
• ArrayCGH: detects imbalances throughout the genome
• Conventional karyotyping: to investigate low level cytogenetic mosaicism, familial cytogenetic rearrangement.
• Cell culture- to facilitate biochemical assays or long term storage.