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FRCPath > Prenatal Cytogenetics > Flashcards

Prenatal Cytogenetics Flashcards

1
Q

Describe the features associated with mosaic trisomy 16

A

IUGR, IUD, preeclampsia, preterm delivery, neonatal death, CHD
Most common trisomy seen in spontaneous abortions

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2
Q

What are the 2 types of Triploidy?

A

Diandry - Type 1 - Double paternal contribution

Digyny - Type 2 - Double maternal contribution

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3
Q

What is the most common form of Triploidy?

A

Type 1 - Diandry - Double paternal contribution

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4
Q

What is the placental presentation of Type 1 Triploidy?

A

Double paternal contribution - Cystic villi that have trophoblastic hyperplasia –> Partial hydatidiform mole

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5
Q

Define Partial Hydatidiform Mole

A

Subtype of Hydatiform mole forming in triploid pregnancy with double paternal contribution - Cystic villi that have trophoblastic hyperplasia

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6
Q

Give 3 scan findings of a Diandric triploidy

A

Symmetrical IUGR,
Structural abnormalities including neural tube defects,
Large, cystic placenta,
Oligohydramnios

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7
Q

What is the risk to the mother in a Diandric triploidy?

A

0.5% risk of a malignant invasive mole

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8
Q

Give 2 mechanisms by which a diandric triploidy may arise

A

Fertilisation by 2 sperm (dispermy),

Normal egg fertilised by a diploid sperm

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9
Q

What is the placental presentation of Type 2 Triploidy?

A

Non-hydropic villi, no evidence of molar placenta, generally small

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10
Q

Give 3 scan findings of a Dygynic triploidy

A

IUGR - often asymmetrical,
Large head,
Oligohydramnios,
Holoprosencephaly

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11
Q

Give 2 mechanisms by which a dygynic triploidy may arise

A

Fertilisation of a diploid egg by a haploid sperm,
Retention of a polar body in a fertilised egg,
Fertilisation of an ovulated primary oocyte,
Fusion of 2 eggs (dieggy) and fertilisation by a haploid sperm

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12
Q

What may explain the different clinical presentations of type 1 and type 2 triploidies?

A

Different imprinted states

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13
Q

Give 3 clinical features of triploidy

A 
Face to chest fusion,
Limb growth/development retardation,
Growth disorganisation,
Midface dysplasia,
Syndactyly,
Heart defects,
Renal defects
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14
Q

What is the most common form of gestational trophoblastic disease?

A

Hydatiform mole

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15
Q

Under WHO classification - give 2 examples of pre-malignant gestational trophoblastic diseases

A

Complete hydatiform mole,

Partial hydatiform mole

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16
Q

Under WHO classification - give 2 examples of Malignant gestational trophoblastic diseases

A

Invasive mole,
Choriocarcinoma,
Placental site trophoblastic tumour

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17
Q

What is the unique biochemical marker in gestational trophoblastic disease?

A

Elevated hCG (human chorionic gonadotrophin) - useful for early detection, diagnosis and follow-up

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18
Q

What causes a Complete Hydatidiform Mole?

A

Diploid androgenetic pregnancy - both chromosome sets paternally derived

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19
Q

Give 3 clinical presentations of complete hydatidiform moles

A

No fetal development,
Extensive hydrops,
Swollen villi and marked widespread hyperplasia of trophoblast,
Maternal hypertension, oedema and vaginal bleeding

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20
Q

What is the recurrence risk following a complete hydatidiform mole?

A

1 in 100 - rising to 1 in 4 following 2 consecutive CHMs

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21
Q

What is the genetic difference between sporadic complete hydatidiform moles and familial recurrent hydatidiform moles?

A

Pregnancies are genetically biparental in origin

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22
Q

Describe Familial recurrent hydatidiform moles

A

Maternal-effect AR condition - very rare,
75% pregnancies develop as CHM
NLRP7 (19q13.42) and KHDC3L (6q13) both thought to have role in maintaining maternal imprinting within the ovum

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23
Q

What is the risk of developing an invasive mole from a complete hydatidiform mole?

A

1-15%

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24
Q

Describe Gestational Choriocarcinoma

A

Bleeding - local disease,
Metasteses - causing symptoms at site
Highly malignant tumour of uterine wall - 3% risk following CHM and 0.1% risk following partial mole,
Increased levels of hCG

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25
Q

Describe Placental Site Trophoblastic Tumour

A

Least common form of GTD - commonly follow normal pregnancy,
Presentation varies from slow growing disease limited to uterus to a more rapidly growing metastatic disease similar to choriocarcinoma
PSTT is diploid and arises from the non-villous trophoblast

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26
Q

What treatment and monitoring is offered following gestational trophoblastic disease?

A

Suction evacuation for partial and complete moles,
Monitor hCG levels for up to 2 years following CHM and 6 months following partial mole,
Pregnancy should be avoided during monitoring

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27
Q

Describe the formation of Oogonia

A

During embryological development, diploid primordial germ cells migrate to embryonic ovary - undergo rapid mitosis –>approx 7 million oogonia

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28
Q

What happens to oogonia following 7th month of gestation?

A

Majority die.

Rest enter meiosis 1 –> primary oocytes progress through first meiotic prophase until diplotene - arrest until puberty

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29
Q

What phase are primary oocytes arrested in until puberty?

A

Diplotene of M1

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30
Q

What happens to primary oocytes at puberty?

A

Groups periodically resume meiosis - by ovulation oocytes are in Metaphase 2 of Meiosis 2

31
Q

When is meiosis complete during oogenesis?

A

After fertilisation

32
Q

During telophase of oogenesis - describe the 2 daughter cells produced

A

Small daughter cell with virtually no cytoplasm - 1st polar body,
Larger cell with nearly entire volume of cell contents - secondary oocyte

33
Q

Describe the secondary oocyte

A

Cytoplasm contains large number of mitochondria, ribosomes, DNA/RNA polymersases, protective chemicals and morphogenic factors.
Plasma membrane surrounded by thick extra cellular matrix - Zona Pellucida - also surrounded by a layer of foccile cells - cumulus cells - nurture the oocyte before and just after ovulation

34
Q

Define fertilisation

A

Process by which an egg and sperm fuse to become a new individual - usually occurs in ampulla of fallopian tube

35
Q

What is the cortical reaction in fertilisation?

A

Cortical granules inside oocyte fuse with plasma membrane of the cell - enzymes inside these granules are expelled by exocytosis to the ZP - causes glycoproteins in the ZP to cross linke –>matrix become impenetrable

36
Q

Why does the zona pellucida degrade in the zygote?

A

Allows implantation of the blastocyst following migration to the uterus

37
Q

Define cleavage

A

Zygote divides repeatedly to form smaller cells (blastomeres) - cell divsions are slow and asynchronous

38
Q

Define rotational cleavage

A

1st division is in the vertical plane, in the second round one cleaves vertically and one horizontally

39
Q

Define compaction

A

Loosely associated blastomeres of 8 cell embryo flatten against each other to form the Morula - tight packaging seals off sphere and outer cells secrete fluid to form hollow ball of cells, inner cells form gap junctions enabling small molecules and ions to pass between them

40
Q

What is the fluid filled cavity in the morula called?

A

Blastocele

41
Q

Describe the blastocyst

A

At 16 cell stage can discriminate cells - outer layer (trophoblast) –>CHORION
Inner non-polar cells congregate at one end of blastocele –> INNER CELL MASS

42
Q

Describe the Inner Cell Mass

A

Goes on to form all cells of the organism plus 3 other extraembryonic membranes; the yolk sac, amnion and allantois

43
Q

What happens if splitting occurs at the blastocyst stage?

A

Monozygotic twins

44
Q

When does implantation occur during embryogenesis?

A

Day 5 - Day 6

45
Q

How does implantation occur during embryogenesis?

A

Day 5: Enzyme released that bores hole through ZP, causes it to partly degrade and releases blastocyst.
Day 6: Blastocyst attaches tightly to uterine epithelium (implantation).
Trophoblast cells rapidly proliferate and differentiate

46
Q

Following implantation what do the trophoblast cells differentiate in to?

A

Inner layer - cytotrophoblast

Multinucleated outer cells layer - Syncytiotrophoblast - invades connective of uterus

47
Q

Describe the differentiation of the Inner Cell Mass prior to implantation into 2 distinct layers

A 
External layer (epiblast or primitive ectoderm), --> Ectoderm, endoderm and mesoderm + 3 extra embryonic membranes
Internal layer (hypoblast or primitive endoderm), --> Extraembryonic mesoderm
48
Q

What are the fluid filled cavities either side of the bilmainar disc?

A

Amniotic cavity and yolk sac

49
Q

Describe gastrulation

A

The orientation of the body is established and the trilaminar disc is formed - occurs in week three, rapid cell movement

50
Q

Describe the trilaminar disc

A

Endoderm, Ectoderm and Mesoderm

51
Q

What tissues does the Ectoderm form?

A

Skin (and derivatives)

Nervous System

52
Q

What tissues does the Mesoderm form?

A

Blood,
Vessels,
Muscular tissue,
Connective tissue

53
Q

What tissues does the Endoderm form?

A 
Lung,
Liver,
Pancreas,
Thymus,
Endocrine glands
54
Q

What is cell-free fetal DNA

A

cffDNA first described by Dennis Lo et al in 1997 is made up of fragments (approx 200-300bp) in the maternal plasma derived from the placenta

55
Q

When can cffDNA be detected in the maternal plasma?

A

From 4-5 weeks, reliably from 7, concentration raises with gestation and is rapidly cleared from the maternal blood stream following delivery

56
Q

Describe 2 challenges associated with distinguishing/isolating cffDNA

A

1) Concentration of cfDNA is low
2) cffDNA only makes up 10-20% of cfDNA
3) Half of fetal genetic material is maternally derived - indistinguishable from cfmDNA

57
Q

Give 3 clinical applications of NIPD

A

1) Fetal sex determination where there is F/H X-linked disease
2) Diagnosis of certain single gene disorders - particularly paternally inherited mutns
3) Detection of fetal aneuploidy
4) Fetal blood typing in RhD-ve mothers

58
Q

Give 3 disorders where sex determination of the fetus by NIPD may be clinically useful

A

1) CAH
2) DMD
3) Adrenoleukodystrophy

59
Q

How is NIPD for fetal sex determination carried out?

A

Blood spun to isolate plasma - circulating nucleic acids isolated and RT-PCR then used to identify SRY - quantitative test

60
Q

How can you avoid false negative results in fetal sex determination by NIPD?

A

Having minimum cutoff for cffDNA present,
Testing for universal fetal markers (paternally derived SNPs or CCR5),
Carry out replicate testing

61
Q

What restricts the identification of large scale abnormalities in NIPT?

A

The fragment lengths of the cffDNA - approx 200-300bp

62
Q

Give 2 examples of placentally expressed genes useful for quantifying fetal fractions in NIPT

A

SERPINB5 - hypomethylated in placenta, hypermethylated in maternal cells,
RASSF1 - hypermethylated in fetal tissue, maternally hypomethylated

63
Q

What is the main limitation of using a hypomethlyated marker in fetal fraction determination in NIPT?

A

Bilufite conversion massively depletes input DNA - use of hypermethylated fetal cells as hypomethylated maternal cells can be removed

64
Q

How can cffDNA be enriched within a sample?

A

Targeting short fragments - maternal fragments tend to be longer

65
Q

Give 2 methods of fetal aneuploidy determination in NIPT

A

1) Targeting fetal specific RNA/DNA

2) Direct measurement of chromosome dosage

66
Q

Give 3 benefits of NIPT/D

A

1) Non-invasive testing much safer - reduce in miscarriage
2) Cheaper for FMUs - less expertise to take blood than an invasive sampling test
3) Potential for earlier diagnosis
4) Less trauma for parents
5) Potential to improve quality of care

67
Q

Give 3 limitations of NIPT/D

A

1) In multiple pregnancies cannot distinguish fetuses
2) Proportion of cffDNA in women with high BMI is reduced - higher false negatives and inconclusives
3) Source of cffDNA is placenta - CPM etc
4) False negatives - vanishing twins, triploidy, low fetal fraction
5) Can be complicated by maternal abnormalities

68
Q

What is DANSR?

A

Digital Analysis of Selected Regions

69
Q

Describe DANSR

A

Enables targeted sequencing of selected loci (SNPs) from specific chrms.
Locus specific DANSR oligos anneal to cfDNA, their terminals form 2 nicks, ligation of these nicks results in product capable of amplification

70
Q

How does DANSR enable estimation of fetal fraction in NIPT?

A

Primers for non-polymorphic loci on target chrms give counts of chrms and primers for polymorphic loci on chrms 1-12 facilitate differentation between maternal and fetal DNA

71
Q

Give 2 types of result to always be reported in prenatal microarray context

A

Any variant that will potentially inform management of pregnancy, high penetrance neuro-suscept loci with severe pheno, Neuro-suscept loci with associated abnormalities that could be seen on scan, unsolicited pathogenic findings

72
Q

Give 3 egs of CNVs not to be reported in prenatal microarray context

A

15q13.1q13.3 Dups, 15q11 BP1-BP2 dels/dups, Xp22.31 (STS) dups, 16p13 dups, heterozygous dels of recessive genes that cannot be linked to phenotype

73
Q

What 2 considerations should be given when writing prenatal microarray reports of uncertain results?

A

Do not include patient support leaflets, clinically actionable unsolicited pathogenic CNVs should include clear comment that they are unrelated to presenting phenotype

FRCPath (9 decks)

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