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

Prenatal Genetics Flashcards

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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
What are the malformations associated with cytomegalovirus
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
26
Why can diabetes be a teratogen
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
27
What birth defects can arise out of diabetes
Macrosomia Cardiac defects – isomerism (flipped heart??)Neural tube defects – spina bifida, anencephaly Cleft lip/palate Limb defects/sacral agenesis Renal abnormalities
28
What is the use of prenatal diagnosis
Used for prenatal and postnatal treatment Preparation for delivery Prognosis Termination of pregnancy Because people want to know
29
What are the challenges/drawbacks regarding prenatal diagnosis
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
30
What are prenatal screening options
Before pregnancy - unusual, screen for recessive and X-linked disease During pregnancy - blood grouping, HB electrophoresis, hepatitis AIDS, syphilis US Combined test NIPT
31
Why is maternal blood testing important
To avoid rhesus disease and identify beta globin variants
32
What is rhesus disease
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
33
How is rhesus disease treated
During pregnancy mother is treated with anti-D immunoglobulin
34
What does Hb electrophoresis identify
Identifies β globin variants - β-thalassaemia, sickle cell Does not identify α globin variants which are diagnosed by microcytic picture in absence of anaemia
35
What is ultrasound used for
Foetal anomaly scan Screening scan
36
What are the drawbacks of ultrasound
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
What is the combined test
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
What is the significance of nuchal translucency
Indicates risk of trisomy 13,18,21, monosomy X, triploidy Congenital heart disease Needs trained individuals
39
What are the false negative rates for nuchal translucency
16% false negatives, 2.2% false positives
40
What are the placental hormones measured
PAPP-A + βHCG
41
What is the significance of placental hormones
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
What is the quadruple test
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
Describe the non invasive prenatal testing
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
What are the uses of ffDNA
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
How is NIPT used to diagnose single gene disorders
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
What are the drawbacks of NIPT
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
What is amniocentesis
When the fluid surrounding the baby i samples after 6 weeks
48
What is chorionic villus sampling
Normally a transabdominal biopsy of the future placenta
49
What are the complications associated with CVS
Placental mosaicism = not representative Trismic rescue to prevent trisomy 16 may occur in the foetus, but trisomy still seen in placental
50
What are the two chromosome analysis methods
QFPCR - trisomy 13,18,21 Karyotype - trisomy, triplication and robertsonian translocation
51
What is QFPCR in regards to prenatal diagnosis
Looks at polymorphic markers from the three trisomy related chromosomes
52
What are the potential results of qfPCR in trisomy investigation
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
What is trismic rescue
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
If trismic rescue results in loss of bi-parental inheritance for a chromosome, what are the consequences
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
What are the key maternal and paternal genes involved in Beckwith-Wiedemann Syndrome
Maternal alleles make H19 & CDKN1C | Paternal alleles make IGF2
56
How can you test for single gene disorders prenatally
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
What can be treated prenatally
Maternal drug Rx: Fetal tachycardia Fetal thyroid disease Fetal Blood transfusion Maternal IVIg : Prevent platelet antibodies Neonatal haemochromatosis Fetal Myasthenia Gravis
58
What are three conditions where you can offer prenatal surgical treatment
Twin –Twin transfusion Diaphragmatic hernia Spina bifida
59
What delivery considerations need to be made
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
Criteria for prenatal diagnosis for termination of pregnancy
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
Ethics
The status of handicapped individuals The status of the foetus Religious views Cultural views Personal views
62
What factors can increase risk of foetal abnormalities
Maternal age - increased risk of trisomy Paternal age - certain single gene disorders Drugs/medication Family history/consanguinity
63
What is the difference between preimplantation genetic diagnosis and screening
Diagnosis - specific abnormality testing for severe genetic disorders Screening - looking for a wide range of major disorders, used to increase IVF success rate
64
What is non invaive prenatal testing
Testing of ffDNA/cf foetal DNA from the maternal blood
65
Where do foetal cells and cell free DNA originate from
The placenta/trophoblast
66
When can you start and then no longer detect ffDNA
From 5 weeks until birth
67
Can you differentiate between foetal and maternal cfDNA
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
What is the T21 detection rate using NIPT
99. 2% detection rate | 0. 09% false positive rate
69
Why use NIPT
Prevents unnecessary invasive tests Makes choice for women easier whether they should take an invasive test or not
70
What is the foetal fraction
Amount of foetal DNA present in maternal blood
71
Why is it important to measure foetal fraction
False results can appear if this is not measured - needs to be above 6%
72
How to correct for foetal fraction
Consider it alongside maternal age
73
Is ffDNA considered alone
No, it is used alongside maternal age and results from the combined test
74
What may impact foetal fraction
Maternal height and weight, twin pregnancy
75
What technology is used for NIPT
NGS
76
What are the potential results of NIPT
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
How can results be accessed
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
What are the advantages of NIPT
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
What are the considerations regarding foetal sex determination
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
In what situations may foetal sex determination be undertaken
X-linked disorder screening Foetal sex aneuploidy screening - Turner's syndrome However, false positive rate is double that of other aneuploidies
81
What is foetal hydrops
Accumulation of fluid in 2 or more extra-vascular spaces
82
What are some of the causes of foetal hydrops
``` CVS Idiopathic - unknown Lymphatic Haematological - anaemia Chromosomal/syndromic Infection Twin-twin transfusion syndrome Thoracic leisons Inborn errors of metabolism Urinary tract malformations ```
83
What test can you use to identify FH by aetiology
Ultrasound
84
What are the benefits to identifying cause of foetal hydrops
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
How is data collated to improve investigation of foetal hydrops
Multi-centre data collection alongside 100K genomes project and exome data
86
What is the FOLD study
Investigation of foetal oedema (hydrops) and lymphatic disorders

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