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![Page 1: David Amor, Victoria Clinical Genetics Services - Implications of New Genetic Technologies on Prenatal Diagnosis](https://reader034.fdocuments.in/reader034/viewer/2022052601/558e93d51a28ab52108b464c/html5/thumbnails/1.jpg)
Implications of new genetic technologies on prenatal diagnosis
5th Annual Obstetric Malpractice Conference
David Amor
21st June 2013
VCGS is a not for profit subsidiary of Murdoch Childrens Research Institute and the main provider of clinical and pathology genetics services in Victoria
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All couples hope for a healthy baby; however human
reproduction is hazardous
• 4% of all babies are born with a congenital abnormality or genetic disorder that is evident at birth
• Most people have at least one recognised genetic disease
• All people are born with a genetic predisposition to various medical problems
• Every genome contains 50-100 variants that are expected to cause genetic disease
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Wrongful birth litigation may occur following birth of a child
with a genetic disorder when
1. A genetic risk was not identified prior to pregnancy
2. A genetic disorder was not detected during the pregnancy
Inheritance Able to detect at risk couples prior to pregnancy
Able to detect during pregnancy
Inherited dominant + +
New dominant - +
Autosomal recessive + +
X-linked + +
Chromosomal +/- +
Polygenic - +/-
Epigenetic - +/-
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Testing technologies and practices
relatively stable (and limited) over
last decade
• Taking a family history
• Down syndrome screening
• CVS and amniocentesis
• Ultrasound
Allowing various reproductive options to be exercised: • TOP
• PGD
• Not have children
• Accept risk
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Uptake of Down syndrome screening in Victoria
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
Nu
mb
ers
scr
ee
ne
d
Year
Proportion of MSS FTS and STS to NBS
NBS
T1 MSS
T2 MSS
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Two new genetic technologies are currently transforming
prenatal diagnosis
1. Chromosome microarray
This technology is transformative because it offers the ability to simultaneously test for large numbers of genes in a cost effective manner
2. Non-invasive prenatal diagnosis (NIPD)
This technology is transformative because it enables examination of fetal DNA without any risk to the fetus
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Three trends is prenatal diagnosis
1. More information
2. Less invasiveness
3. Less certainty about results
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Microarrays in prenatal diagnosis
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Microarray
(molecular karyotype)
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• Copy Number (LogR)
• Genotyping data (B-Allele Frequency, BAF)
a-C
GH
SN
P-a
rray
Molecular Karyotyping
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Challenges of chromosome microarray in prenatal
diagnosis
1. Many variants with incomplete penetrance
2. Many variance of uncertain significance
3. Genome wide test = incidental findings
4. Knowledge constantly evolving
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• 4406 women (various indications)
• Detected by karyotype and microarray
374/4406 (8.7%)
• Detected by karyotype only
40 balanced rearrangements
17 triploidy (CGH arrays)
• 1.5% results of uncertain significance
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Wapner et al., NEJM
• VCGS pilot study of pregnancies with ultrasound abnormality showed similar result
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Ethical complexities of prenatal microarray
• Detecting CNVs of uncertain clinical significance (1.5%) raises ethical
considerations.
• Need to consider the potential harm to a woman or her fetus
• Is it ethically justifiable to withhold test result information from a woman?
• What constitutes an 'informed choice' when women are offered microarray in pregnancy?
• Are clinicians responsible for 'unnecessary' termination of pregnancy?
• Need to support the autonomy of women and their right to information from microarray in order to make informed choices about their pregnancies.
• Non-directive pre-test and post-test genetic counselling is central to the delivery of these ethical objectives
McGillivray et al. Prenatal Diagnosis 2012
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Non invasive prenatal screening (NIPS)
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Non invasive prenatal screening (NIPS)
• Using fetal DNA from maternal
blood
• Initially limited to USA, China and
Hong Kong
• Available in Australia since early
2013 through multiple pathology
providers
• Cost $850-$1250
• Currently only capable of detecting
DS and small number of other
abnormalities
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NIPS by Massively Parallel Sequencing
Taken from Bianchi Nat Med 2012
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VCGS - NIPS Pilot Study (n = 38)
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Sequenom1,2
Verinata 3
Ariosa4,5,6
Natera
Trisomy 21
(Down Syndrome) 98.6-99.1% 0.2%
99.9% 0.2%
100% 0.1%
>99% 0%
Trisomy 18
(Edwards Syndrome) 100% 0.3%
97.4% 0.4%
98% 0.1%
>99% 0%
Trisomy 13
(Patau Syndrome) 91.7% 0.9%
87.5% 0.1%
80% 0.05%
>99% 0%
45,X
(Monosomy X) Not evaluated 95.0% 1.0%
Not evaluated 92% 0%
(1) Palomaki GE et al. Genet Med 2011 (2). Palomaki GE et al. Genet Med 2012 (3) Bianchi DW et al, Obstet Gynecol 2012
(4)Ashoor G et al. AJOG 2012 (5) Nicolaides et al. AJOG 2012 (6) www.ariosadx.com
Detection Rate False Positive Rate
Non-Invasive Prenatal Screening
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American College of Obstetricians and Gynaecologists:
Recommends NIPT as one of the options that can be used as a primary screening tool for women at increased risk for aneuploidy and for women with and increased risk result from first or second
maternal serum screening
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NIPS - Key Points:
• A new name:
“NIPS is a very accurate screening test”
• Key Advantage:
It is minimally invasive, the detection rate is higher, the NPV is greater, and the FPR is
lower
• False positives and the need for confirmation:
These reports strongly state that positive results should be followed-up with an invasive
diagnostic test before any decision is made regarding pregnancy termination
• Emphasis on counselling:
“Health Care Practitioners should provide patients with both pre-test and post-test
counselling with the goal of avoiding patient harm or confusion - I can’t stress this
enough [Anthony Gregg, MD, FACOG, FACMG]”
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The future?
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Concluding points
• Testing capabilities have outstripped our ability to counsel and interpret information
• Pace of change is extremely rapid – when does a test become ‘standard of care’ and how will this be judged retrospectively?
• Multiple testing options replacing small numbers of mature tests
• Informed choice and consent
• Incidental findings and findings of uncertain significance
• Multiple testing brings increased risks of false positive results and risk of terminating a healthy pregnancy
• Interpretation of results is still evolving
• No funding mechanisms in place
• Insufficient resources for counselling
• Ethical issues
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