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Prenatal Testing for Chromosomal Conditions Flashcards

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1
Q

What is the most common cause of trisomy 21?

A

Non-disjunction in meiosis I causes ~65% of all cases

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2
Q

What is nuchal translucency?

A

A measure of the thickness of fluid accumulated under the skin on the back of the foetal neck, as visualised on ultrasound

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3
Q

When is the ultrasound to measure nuchal translucency performed? What is normal nuchal translucency?

A

Performed between 11 and 14 weeks

“Normal” thickness <~3mm

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4
Q

What is the detection rate of nuchal translucency measurement for trisomy 21? What is the detection rate of combined 1st trimester screening?

A

Nuchal translucency alone detects ~70% (or less) of trisomy 21 cases
Combined 1st trimester screening detects 85-90% of cases

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5
Q

How does nuchal translucency change over the course of a pregnancy?

A

Nuchal translucency is dependent on gestational age and usually spontaneously decreases as pregnancy progresses

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6
Q

What 4 analytes are measured in 2nd trimester maternal screening?

A

a-fetoprotein
Oestriol
hCG (free B-subunit)
Inhibin A

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7
Q

In the 2nd trimester maternal serum screening test, what are the analytes results that give an increased risk for trisomy 21?

A

Decreased AFP, oestriol

Increased hCG, inhibin A

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8
Q

What does the 1st trimester screening test involve?

A

Nuchal translucency measurement and biochemical maternal serum screening
Other factors are also taken into account when calculatin the final result

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9
Q

What 2 analytes are measured in 1st trimester maternal screening?

A

Pregnancy-associated plasma protein A (PAPP-A)

hCG (free B-subunit)

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10
Q

In the 1st trimester maternal serum screening test, what are analytes results that give an increased risk for trisomy 21?

A

Decreased PAPP-A

Increased hCG

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11
Q

In the 1st trimester maternal serum screening test, what are analytes results that give an increased risk for trisomy 18?

A

Decreased PAPP-A and hCG

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12
Q

What other factors are taken into account when calculating a result from 1st trimester combined screening?

A

Woman’s age at estimated due date (EDD)
Woman’s weight
Age of gestation

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13
Q

List 5 reasons why a woman might choose to have prenatal screening

A

Reassurance when result is normal
Provides risk information for couples who otherwise would not choose to begin a pregnancy
Gives couple a choice of termination of affected foetus
Allows couple to prepare psychologically for affected baby
Helps doctor plan delivery, management and care of affected baby

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14
Q

List 3 reasons why a woman might choose not to have prenantal screening

A

Might not wish to know prior to birth
Termination may be unacceptable for religious, moral or cultural reasons
May have concerns about miscarriage due to CVS or amniocentesis

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15
Q

What are the 2 main sampling procedures used to obtain foetal cells for karyotyping and what does each involve?

A

CVS: needle is used to obtain a sample of tissue (chorionic villi) from the developing placenta either transabdominally or transcervically (under ultrasound)
Aminocentesis: needle inserted transabdominally to obtain amniotic fluid (20mL) containing foetal cells (under ultrasound)

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16
Q

When is CVS performed?

A

From 11 weeks gestation

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17
Q

When is amniocentesis performed?

A

From 15 weeks gestation

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18
Q

What is the risk of miscarriage with CVS?

A

Procedure is invasive and carries a risk of miscarriage 1% above background 2.5% (which increases with maternal age)

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19
Q

What is the risk of miscarriage with amniocentesis?

A

Procedure is invasive and carries a risk of miscarriage 0.5% above 0.7% background (which increases with maternal age)

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20
Q

What is the karyotype of a carrier of a balanced Robertsonian translocation?

A

45,XX,der(14;21)(q10;q10)

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21
Q

Robertsonian translocations are produced by the fusion of which class of chromosomes?

A

Acrocentric (between 2 long arms at or near the centromere)

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22
Q

What does q10 refer to in all chromosomes?

A

The position of the centromere

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23
Q

What are the 2 broad classes of chromosomal abnormalities?

A

Numerical (aneuploidies, involving the number of chromosomes)
Structural (involving breakage or rearrangement)

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24
Q

What is the normal diploid number of chromosomes?

A

46 (2n)

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25
What are cells with 69 (3n) chromosomes called? What usually happens in this case?
Triploid | Foetus usually miscarries early
26
What is a reciprocal translocation?
Exchange of material between 2 non-identical chromosomes
27
What is an inversion? What is the difference between a paracentric and pericentric translocation?
Inversion of a segment of chromosome material within the same chromosome Pericentric involves the centromere, paracentric does not
28
What is a ring chromosome?
Joining of 2 ends of the same chromosome
29
What is an isochromosome?
Chromosome with identical long or short arms resulting from horizontal splitting of the centromere
30
What is a derivative chromosome?
Abnormal chromosome generated by more than one rearrangement within a single chromosome (e.g. an inversion and deletion of the same chromosome), or rearrangements involving two or more chromosomes (such as the unbalanced products of a translocation)
31
What is a marker chromosome?
An abnormal chromosome in which no part can be identified
32
What is the convention in karyotype nomenclature?
Give the number of chromosomes first, followed by the types of sex chromosomes, followed by the types of additional, missing or abnormal chromosomes Chromosomal rearrangements are described by noting the rearrangement and indicating the breakpoint or breakpoints
33
Karyotype: female with Down syndrome
47,XX,+21
34
Karyotype: male with trisomy 18
47,XY,+18
35
Karyotype: Turner syndrome
45,X
36
Karyotype: Klinefelter syndrome
47,XXY
37
Karyotype: Mosaic Turner syndrome
45,X/46,XX
38
Karyotype: deletion of the short arm of Ch 4 with breakpoint at band p15
46,XX,del(4)(p15)
39
Karyotype: inversion of Ch 2 with breakpoints at p12 and q12
46,XY,inv(2)(p12q12)
40
Karyotype: male with ring Ch 13
46,XY,r(13)
41
Karyotype: balanced translocation between Ch 3 and Ch 9, with breakpoints at band p14 and q21 respectively
46,XX,t(3;9)(p14,q21)
42
Karyotype: female with a duplication of the segment between bands 13 and 14 on the short arm of Ch 5
46,XX,dup(5)(p13p14)
43
Karyotype: female with one normal X Ch and an isochromosome of the long arm of the other X Ch
46,X,i(Xq)
44
Karyotype: 1 copy of Ch 3 is replaced by a derivative Ch from a translocation between Ch 3 and Ch 9 (breakpoints at p14 and q21 respectively) Why would this occur?
46,XY,der(3)t(3;9)(p14;q21) | Would occur due to segregation at meiosis from a balanced t(3;9) to give unbalanced products
45
What chromosomal abnormality results in cri du chat syndrome? List 5 common symptoms. How does this syndrome occur?
Deletion of short arm of Ch 5 from band p14 to the end of the p arm Crying of affected baby sounds like a mewing cat, there are distinctive facial features, microcephaly, heart defects and moderate to severe intellectual disability Most cases are sporadic but 5-10% are offspring of translocation carriers
46
What are CNVs?
Copy number variants are defined as segments of DNA ranging in size from 1000bp (a Kb) to several million bp (a Mb) that have been shown to vary in copy number between individuals in a population Can be copy number losses (deletions) or gains (duplications), and because of their size they often contain or overlap 1 or more genes as well as their regulatory regions
47
How much of the human genome is estimated to be affected by CNVs? How many CNVs are there per individual genome? What is the median size of a CNV?
~5% ~800-1000 CNVs per individual genome Median size of 34Kb
48
What % of copy number differences between any 2 individuals are accounted for by common CNVs (with population frequency >5%)?
80%
49
What kinds of pathological processes have CNVs been associated with?
Complex disease susceptibility | Phenotypic abnormality in many sporadic and neurodevelopmental/neurobehavioural conditions
50
What are the 3 advantages of molecular karyotyping (chromosome microarray analysis) over conventional cytogenetics?
Resolution of microarrays is 10-1000x greater (capable of detecting CNVs as small as 5-10Kb in length) Information of gene content and more precise breakpoints to assist with clinical interpretation May be used to clarify significance of abnormal G-banding results
51
What is the resolution of G-banded karyotyping?
5-10Mb
52
What the 3 the main limitations of CMA? Are these always significant?
Truly balanced chromosome rearrangements (e.g. translocations, insertions, inversions, etc.) are not detectable (may not be significant as truly balanced rearrangements are relatively infrequent (<0.1%) causes of abnormal phenotypes in the population) Does not provide positional information of copy number gains, which can be relevant to risk of recurrence May not detect mosaicism of an abnormal cell line below 20% (but detection of mosaicism below this is sometimes possible depending on the origin of the error, i.e. mitotic vs. meiotic, and the array design)
53
In what % of patients with developmental delay, ASD and multiple congenital abnormalities does molecular karyotyping identify pathogenic CNVs? Is this better or worse than conventional karyotyping?
15-20% | Achieving an actual diagnostic result using CMA is on average 12% greater than that achieved by classical cytogenetics
54
In what presentations is CMA recommended as a first tier test for investigation?
Developmental delay, ASD and multiple congenital abnormalities
55
What are the 2 main types of genomic microarrays in use?
Array-CGH (comparative genome hybridisation) | SNP-array
56
What are the steps involved in performing and interpreting array-CGH?
Test and reference genomic DNA is fragmented and differentially labelled with Cy3 (test, green) and Cy5 (reference, red) dyes Labelled samples are combined and hybridised to an array containing thousands of oligonucleotide probes During hybridisation, test and reference DNA compete for binding to the array surface Relative intensity of fluorescence for each probe is calculated (yellow spots indicate equal amounts present) and represented graphically Ratio thresholds are used to define 2-copy (normal for autosomal chromosome regions), 1-copy (loss) and 3-copy (gain) calls
57
What are the steps involved in performing and interpreting SNP-array?
Test genomic DNA is fragmented, amplified by PCR and hybridised to a SNP-array Each SNP target is examined by a minimum of 2 unique allele-specific oligonucleotide probes Following hybridisation of target sequences, bound fragments are stained with a dye (FAM), quantified using an array scanner and probe ratios calculated by normalising to data obtained for a reference standard
58
What is the advantage of a SNP-array over an array-CGH?
SNP-arrays provide both copy number (red line) and genotyping (blue dots) information (homozygous are displayed at bottom and top, while heterozygous are in the middle of the ratio plot) The allelic copy number enables detection of copy-number neutral loss of heterozygosity (LOH) and also provides independent validation of gains and losses
59
What are the 4 main categories of CNVs seen in the diagnostic setting and their relative frequencies?
1) Clearly polymorphic without clinical significance (~70%) 2) Clearly pathogenic (~12%) 3) Significance unknown (~15%) 4) Susceptibility (risk) locus (~3%)
60
How might GPC3 relate to findings of cleft lip and palate, diaphragmatic hernia, large cysts on kidneys and ventriculomegaly of the brain in a 19 week foetus on ultrasound?
Mutation in this gene can cause craniofacial, skeletal, cardiac and renal abnormalities including pre- and post-natal overgrowth, coarse facies and congenital heart defects
61
What syndrome is caused by a mutation in GPC3? What are the outcomes for a foetus with this syndrome?
Simpson-Golabi-Behmel syndrome | Severe cases are life-threatening before birth or in infancy
62
What is the basis of non-invasive prenatal testing (NIPT)?
Some cell-free DNA from the foetus (cfDNA, predominantly from villous trophoblasts in the placenta) is released to the mother's circulating blood in each pregnancy
63
How big are fragments of cfDNA in the maternal bloodstream?
Small (150-200bp, some as short as 25-50nt)
64
Is foetal cfDNA the only DNA sequenced in NIPT?
No, maternal cfDNA is also present in the bloodstream and is analysed during NIPT
65
What is massive parallel sequencing?
Sequencing involving very fast high-throughput sequencing of fragments of DNA, generating millions of "reads"
66
What is the basis of high-throughput pyrosequencing?
Chemiluminescent enzymatic reactions of DNA amplified on microbeads (ATP is generated after incorporation of dNTPs into the growing strand of DNA and is used to catalyse a reaction which generates light)
67
What is the basis of high-throughput sequencing using Illumina?
Sequencing of fluorescently labelled DNA fragments that are amplified in clusters on a flowcell substrate Utilises bridge amplification
68
What is the basis of Ion Torrent sequencing?
Involves sequencing reactions that release protons for detection
69
What is the basis of SMRT sequencing?
Slightly different sequencing reaction more akin to normal DNA replication, with each DNA molecule sequenced and detected in its own well (a nanotechnological approach)
70
Which high-throughput sequencing platforms use an optical tag on the nucleotides during the sequencing reaction?
Illumina | SMRT sequencing
71
Where is NIPT performed in Australia?
Currently blood is collected in Australia but is sent overseas (USA and China) for testing
72
When is foetal cfDNA present in sufficient quantities in the maternal blood for NIPT?
9-10 weeks gestation
73
What % of cfDNA in a sample must be of foetal origin for NIPT to be performed? In what % of cases can a result not be obtained because of insufficient foetal cfDNA (low foetal fraction)?
1-4% cfDNA must be of foetal origin | In 1-7% of cases, there is insufficient foetal cfDNA for testing
74
What is whole genome sequencing in NIPT used for?
For molecular counting for detection of foetal aneuploidy
75
What is targeted (or directed) sequencing in NIPT used for?
Also does molecular counting but "targets" (using multiplex PCR) the specific chromosomes of interest and only sequences, analyses and reports on these
76
What is SNP targeted (or directed) sequencing in NIPT used for?
Also does molecular counting, and analyses 20,000 SNPs on specific chromosomes in foetal and maternal cfDNA (adds greater discriminatory power)
77
NIPT is currently being recommended as a screening test for trisomy 21, rather than replacement for diagnostic tests. Why?
High-risk NIPT results should be confirmed by invasive cytogenetic testing because of the PPV being low (one estimate is 50-90%) Scope of testing with regards to what can be detected on using NIPT is smaller compared with whole chromosome analysis cfDNA is mostly derived from cytotrophoblast tissue, which may produce false positive results
78
When is maternal blood taken for 1st trimester biochemical maternal serum screening?
10-12 weeks

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