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

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

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 - +/-

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

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

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

Three trends is prenatal diagnosis

1. More information

2. Less invasiveness

3. Less certainty about results

Microarrays in prenatal diagnosis

Microarray

(molecular karyotype)

• Copy Number (LogR)

• Genotyping data (B-Allele Frequency, BAF)

a-C

GH

SN

P-a

rray

Molecular Karyotyping

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

• 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

Wapner et al., NEJM

• VCGS pilot study of pregnancies with ultrasound abnormality showed similar result

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

Non invasive prenatal screening (NIPS)

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

NIPS by Massively Parallel Sequencing

Taken from Bianchi Nat Med 2012

VCGS - NIPS Pilot Study (n = 38)

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

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

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]”

The future?

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