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Clinical Applications of Genomics in Rare Disease and Cancer > Prenatal Genetics > Flashcards

Prenatal Genetics Flashcards

1
Q

What is a teratogen

A

Any substance, agent, or process that induces the formation of developmental abnormalities in a foetus

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2
Q

What are the 3 developmental periods

A

Preorganogenetic (conception – 2.5 weeks)

Active organogenesis (3-8 weeks)

Foetal period (>8 week)

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3
Q

Why do you need to consider the developmental period in relation to teratogens

A

The ability of a teratogen to cause malformations is dependent on the developmental stage of the embryo

The peak susceptibility to teratogens occurs 3-8 weeks post conception during which organ primordia are being formed (critical periods)

Some organs continue to develop after this period (notably the brain)

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4
Q

Through what extra-embryonic organ do teratogens need to pass to affect the foetus

A

The placenta

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5
Q

What are some examples of teratogens

A

Medicine - anticonvulsants

Drugs - alcohol

Infection - rubella, CMV

Medical - diabetes

Diet - folic acid/vit D deficiency

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6
Q

What consequences can anti-epileptic drugs have

A

Exposure in first trimester = higher risk

Behavioural and cognitive problems

Damage dependent on dose on how long it was taken throughout pregnancy

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7
Q

What is FACS

A

Foetal Anticonvulsant Syndrome

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8
Q

What is Foetal Anticonvulsant Syndrome

A

The term foetal anticonvulsant syndrome (FACS) is used when referring to children who have suffered adverse effects after being exposed to anti-epileptic drugs (AEDs) in utero

FACS encompasses major and minor congenital malformations, dysmorphic facial features, and learning or behavioural problems

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9
Q

What is the risk of malformation after exposure to antiepileptic drugs

A

2-3x greater

Risk increases with number and dose of anticonvulsant

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10
Q

What are the confounding variables associated with use of anti-epileptic drugs and pregnancy

A

Epilepsy and seizures - not good, which bring up comorbidities

Use of other teratogens

AED affects folic acid metabolism

AED users may be socially disadvantageous such as re. ability to work

Family history

IQ

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11
Q

What are the features of FACS

A

The anticonvulsant face (teratogenic face?), metopic ridge (suture in centre of forehead), ocular hypertelorism (wide spaced eyes), infraorbital grooves (under eye creases), depressed nasal bridge, long smooth philtrum, thin upper lip

Other features; nail hypoplasia, digital anomalies, developmental delay (almost invariably mild), behavioural problems

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12
Q

What is the relationship between AED’s and IQ

A

Recent study suggests VPA (sodium valproate) has a general effect on IQ

Malformation might not influence developmental delay

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13
Q

What malformations are increased due to exposure to AED’s

A

Cleft lip, malformations of the ear/neck/face, and spina bifida (nearly 15x more likely after exposure to AEDs)

Defects in neural tube, heart, limbs, genitourinary system and skin (VPA)
May rarely affect brain, eye, respiratory tract and abdominal wall (VPA)

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14
Q

Why is VPA dangerous of various AED drugs

A

It shows highest rate of malformation

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15
Q

Why can’t pregnant women simply stop taking AED’s

A

Having a seizure can be fatal

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16
Q

What are the mechanisms causing birth defects due to anticonvulsants/AED’s

A

Reduction of folic acid

Oxidative stress

Inhibition of histone deacetylase

Altered lipid metabolism

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17
Q

What are other teratogens

A 
Warfarin
Retinoic acid
Tetracycline
Thalidomide
Carbimazole
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18
Q

Why is Warfarin a teratogen

A

Causes phenotype of nasal hypoplasia with stippling of epiphyses

Similar to phenotype seen with Vit K deficiency and chondrodysplasia punctata

Mechanism therefore likely to be through warfarin’s therapeutic mechanism – vitamin K dependent post-translational modification of various proteins

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19
Q

How is warfarin involved in vitamin K

A

ANS

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20
Q

What is foetal alcohol syndrome

A

Pre and postnatal growth retardation, characteristic face (cf FACs face), microcephaly, congenital heart disease, developmental delay, behavioural difficulties – autistic spectrum, food aversion

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21
Q

What effects can smaller quantities of alcohol cause

A

Alcohol related neurodevelopmental delay

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22
Q

What is rubella

A

Classical triad of cataracts, cardiac malformation and deafness - skin rash may be present at birth

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23
Q

What are the risks of malformation associated with rubella

A

Risk of malformation related to timing of exposure

First trimester – foetal loss or severely affected including neurodevelopmental problems (>80%)

Second or third trimester – variable outcome but possibility of hearing loss

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24
Q

What is cytomegalovirus

A

More common cause of intrauterine infection, mild illness – woman may not be aware of infection

In 80% will be no effect on developing foetus

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25
Q

What are the malformations associated with cytomegalovirus

A

May result in growth retardation, hearing loss, retinal pigmentation – visual problems, microcephaly/ventricular dilatation, brain calcification (as a consequence of inflammation)

More common as cause of delay than Down syndrome

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26
Q

Why can diabetes be a teratogen

A

Poorly controlled diabetes associated with increased risk of wide range of birth defects

Prevalence of pre-gestational diabetes in mothers of babies with birth defects is significantly increased (4 fold)

Some evidence that gestational diabetes also increases risk of birth defects

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27
Q

What birth defects can arise out of diabetes

A

Macrosomia

Cardiac defects – isomerism (flipped heart??)Neural tube defects – spina bifida, anencephaly

Cleft lip/palate

Limb defects/sacral agenesis

Renal abnormalities

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28
Q

What is the use of prenatal diagnosis

A

Used for prenatal and postnatal treatment

Preparation for delivery

Prognosis

Termination of pregnancy

Because people want to know

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29
Q

What are the challenges/drawbacks regarding prenatal diagnosis

A

Mostly no family history

US can only detect some abnormalities and phenotypes less specific than postnatally

Some problems only detectable late in pregnancy

DNA diagnosis can be very slow

Time is limited

Very stressful for parents

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30
Q

What are prenatal screening options

A

Before pregnancy - unusual, screen for recessive and X-linked disease

During pregnancy - blood grouping, HB electrophoresis, hepatitis AIDS, syphilis

US

Combined test

NIPT

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31
Q

Why is maternal blood testing important

A

To avoid rhesus disease and identify beta globin variants

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32
Q

What is rhesus disease

A

This occurs when a Rh-ve mother has a Rh+ve child

The affects occur for the second Rh+ve child where the maternal antibodies attac the RH+ve cells

Treated with anti-D immunoglobulin

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33
Q

How is rhesus disease treated

A

During pregnancy mother is treated with anti-D immunoglobulin

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34
Q

What does Hb electrophoresis identify

A

Identifies β globin variants - β-thalassaemia, sickle cell

Does not identify α globin variants which are diagnosed by microcytic picture in absence of anaemia

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35
Q

What is ultrasound used for

A

Foetal anomaly scan

Screening scan

36
Q

What are the drawbacks of ultrasound

A

Gestation dependent

Difficulty with resolution
Polydactyly at 12 weeks

Structure not developed enough to identify
Cerebellar vermis

Can only identify by secondary abnormalities - e.g. bladder not visualised despite frequent urination = absent kidneys

37
Q

What is the combined test

A

11 weeks + 3 days and 13 weeks + 5 days = NT + PAPP-A + βHCG + maternal age

NT = nuchal translucency

PAPP-A + βHCG = placental hormones

Taking into account maternal age

38
Q

What is the significance of nuchal translucency

A

Indicates risk of trisomy 13,18,21, monosomy X, triploidy

Congenital heart disease

Needs trained individuals

39
Q

What are the false negative rates for nuchal translucency

A

16% false negatives, 2.2% false positives

40
Q

What are the placental hormones measured

A

PAPP-A + βHCG

41
Q

What is the significance of placental hormones

A

Different ratios indicate different ratio’s - results expressed as MoM (multiple of the mean)

Down’s syndrome - less PAPP-A , increased βHCG

Patau’s and Edward’s - less of both PAPP-A + βHCG

42
Q

What is the quadruple test

A

16-18 week test

AFP, βHCG uE3 (oestrogen),Inhibin A

AFP = initially noted to be high in babies with spina bifida

These babies also were noted to have a lemon shaped skull

Babies with Down’s syndrome have low AFP

43
Q

Describe the non invasive prenatal testing

A

Free placental DNA in maternal circulation. (ffDNA)

Found in plasma fraction of blood

Majority of free DNA is of maternal origin (fmDNA)
↑ ffDNA with ↑ gestation (fetal fraction)
ffDNA shorter fragments than fmDNA

44
Q

What are the uses of ffDNA

A

Foetal sexing - when child at risk of an X-linked disease e.g. DMD
If there is a Y chromosome in mothers blood it shows it is the ffDNA
X-linked disorders mainly affect males

Single gene disorders

Trisomy screening

Rhesus disease

High risk pregnancies - placental disease

45
Q

How is NIPT used to diagnose single gene disorders

A

De Novo Mutations - suitable only if there are few genes associated with disease

Foetal sexing in X –Linked disorders

Dominant disorders with father affected

Recessive compound heterozygote mutations

46
Q

What are the drawbacks of NIPT

A

High demand for Downs screening
Result for Down’s needs to be confirmed by invasive test

Women would like it for many other indications BUT not total reliable

DNA is of placental origin - what about placental mosaicism?

Foetal fraction (amount of ffDNA) may be low

If very high NT despite normal NIPT you still require CVS if normal as high risk of other abnormalities

False +ve with mother suffering from cancer

47
Q

What is amniocentesis

A

When the fluid surrounding the baby i samples after 6 weeks

48
Q

What is chorionic villus sampling

A

Normally a transabdominal biopsy of the future placenta

49
Q

What are the complications associated with CVS

A

Placental mosaicism = not representative

Trismic rescue to prevent trisomy 16 may occur in the foetus, but trisomy still seen in placental

50
Q

What are the two chromosome analysis methods

A

QFPCR - trisomy 13,18,21

Karyotype - trisomy, triplication and robertsonian translocation

51
Q

What is QFPCR in regards to prenatal diagnosis

A

Looks at polymorphic markers from the three trisomy related chromosomes

52
Q

What are the potential results of qfPCR in trisomy investigation

A

The markers are seen as peaks

2 peaks = 2 alleles
If they are equal heights = normal biallelic
If one is larger = trsimic, biallelic

3 peaks = 3 alleles = trismic triallelic

One marker = uninformative

53
Q

What is trismic rescue

A

The cell kicks out a copy of an extra chromosome - but this means that you could inadvertently result in both pairs of chromosomes being from a single parent

54
Q

If trismic rescue results in loss of bi-parental inheritance for a chromosome, what are the consequences

A

If arised from meiotic I error the duplicates are different = heterodoxy

If arisen from meiotic II error = same = isodisomy = can lead to AR disease

Also it may lead to imprinting disorders e.g. if it occurs in Chr 11 or 15

55
Q

What are the key maternal and paternal genes involved in Beckwith-Wiedemann Syndrome

A

Maternal alleles make H19 & CDKN1C

Paternal alleles make IGF2

56
Q

How can you test for single gene disorders prenatally

A

Known family history = CVS/amniocentesis, testing is more accurate

New diagnosis -
Is there only one possible mutation or gene - single gene testing e.g. achondroplasia, cystic fibrosis
Is it in a specific ethnic group
Can you limit to gene panel - tuberous sclerosis
Unknown/large number of possibilities - exome/larger panels

57
Q

What can be treated prenatally

A

Maternal drug Rx:
Fetal tachycardia
Fetal thyroid disease

Fetal Blood transfusion

Maternal IVIg :
Prevent platelet antibodies
Neonatal haemochromatosis
Fetal Myasthenia Gravis

58
Q

What are three conditions where you can offer prenatal surgical treatment

A

Twin –Twin transfusion

Diaphragmatic hernia

Spina bifida

59
Q

What delivery considerations need to be made

A

Delivery in a tertiary centre - congenital heart disease, exomphalos, diaphragmatic hernia

Mode of delivery - casaerean - hydrocephalus, achondroplasia, overgrowth syndromes

Prepare for postnatal complications and mentally prepare parents e.g. show pictures of cleft lip

60
Q

Criteria for prenatal diagnosis for termination of pregnancy

A

Serious disease without effective treatment
Accurate SAFE test
Abortion is acceptable to the couple

<24 weeks legal for psychological/physical reasons

> 24 weeks only when there is significant risk of abnormality

61
Q

Ethics

A

The status of handicapped individuals

The status of the foetus

Religious views

Cultural views

Personal views

62
Q

What factors can increase risk of foetal abnormalities

A

Maternal age - increased risk of trisomy

Paternal age - certain single gene disorders

Drugs/medication

Family history/consanguinity

63
Q

What is the difference between preimplantation genetic diagnosis and screening

A

Diagnosis - specific abnormality testing for severe genetic disorders

Screening - looking for a wide range of major disorders, used to increase IVF success rate

64
Q

What is non invaive prenatal testing

A

Testing of ffDNA/cf foetal DNA from the maternal blood

65
Q

Where do foetal cells and cell free DNA originate from

A

The placenta/trophoblast

66
Q

When can you start and then no longer detect ffDNA

A

From 5 weeks until birth

67
Q

Can you differentiate between foetal and maternal cfDNA

A

No

Maternal DNA is at higher quantities so you compare chromosome numbers to the majority - if there’s an outlier e.g. trisomy, and the mother has no symptoms it may be the foetus’s

68
Q

What is the T21 detection rate using NIPT

A
  1. 2% detection rate

0. 09% false positive rate

69
Q

Why use NIPT

A

Prevents unnecessary invasive tests

Makes choice for women easier whether they should take an invasive test or not

70
Q

What is the foetal fraction

A

Amount of foetal DNA present in maternal blood

71
Q

Why is it important to measure foetal fraction

A

False results can appear if this is not measured - needs to be above 6%

72
Q

How to correct for foetal fraction

A

Consider it alongside maternal age

73
Q

Is ffDNA considered alone

A

No, it is used alongside maternal age and results from the combined test

74
Q

What may impact foetal fraction

A

Maternal height and weight, twin pregnancy

75
Q

What technology is used for NIPT

A

NGS

76
Q

What are the potential results of NIPT

A

Low risk = no further action

High risk (>95% risk for Down’s) = CVS/Amnio

Test failure - no call result
Logistics - posting, DNA loss, tube cracking thus DNS integrity lost
Low foetal fraction
High cell turnover

77
Q

How can results be accessed

A

Portal for easy and secure exchange of patient results
Eliminate sample mixing

Sample tracking
Can find if there is a lost sample if tracking looks odd

Each lab has access to the portal to manage their own clinic users
Immediate update of the portal

Queries and documentation

78
Q

What are the advantages of NIPT

A

Pragmatic and effective - detects majority of trisomy’s

NIPT can be done anywhere as it is simply sent to the lab

Safe and sensitive - not at all like having a needle inserted into the uterus

Cheaper than CVS/amnio

Results within 3-5 days

Keeps money in the NHS

79
Q

What are the considerations regarding foetal sex determination

A

Sex determination is different from trisomy detection as this is mostly not medical in nature

Having this option widely at various stages gives rise for the option for population sex selection

80
Q

In what situations may foetal sex determination be undertaken

A

X-linked disorder screening

Foetal sex aneuploidy screening - Turner’s syndrome
However, false positive rate is double that of other aneuploidies

81
Q

What is foetal hydrops

A

Accumulation of fluid in 2 or more extra-vascular spaces

82
Q

What are some of the causes of foetal hydrops

A 
CVS
Idiopathic - unknown
Lymphatic
Haematological - anaemia 
Chromosomal/syndromic
Infection
Twin-twin transfusion syndrome
Thoracic leisons
Inborn errors of metabolism
Urinary tract malformations
83
Q

What test can you use to identify FH by aetiology

A

Ultrasound

84
Q

What are the benefits to identifying cause of foetal hydrops

A

Genetic cause - information and advice

Future patients - better know how to diagnose and prognosticate, determine risk for future children/family members and better management

85
Q

How is data collated to improve investigation of foetal hydrops

A

Multi-centre data collection alongside 100K genomes project and exome data

86
Q

What is the FOLD study

A

Investigation of foetal oedema (hydrops) and lymphatic disorders

Clinical Applications of Genomics in Rare Disease and Cancer (10 decks)

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