Genomics and pre-natal screening

Damien Bruno PhD

Translational Genomics Unit Head &

Deputy Laboratory Director

VCGS

Australian Bureau of Statistics

Genomics and Perinatal Care. Bodurtha et al. NEJM 2012

• Broadening indications (….-> whole genome)

• Greater complexity (options, choices, informed consent, parental anxiety, commercial interests)

• Increasing diagnostic accuracy

• Acceptance into clinical practice • Professional guidelines and best practice lagging behind uptake• Delay in access to public funding (equity of access issue)

Into the maelstrom

Blood Tests Invasive (samplefetus with needle!)

Spectrum of Prenatal Tests

2.56 Mb deletion 22q11.21arr 22q11.21(17,224,632-19,792,353)x1(DiGeorge / Velocardiofacial syndromes)

FISH: 22q11.2 deletion

del(22)(q11.2q11.2)

• truncus arteriosus (CVS)

1.7 Mb deletion 2q13[hg19] arr 2q13(111,395,603-113,093,928)x1

Rare deletion, de novo, absence of any published clinico-genotype correlations

Issues/Complexities:

- Variants of unknown or uncertain significance- Incidental findings- Consanguinity- Late onset conditions - Informed consent - Targeted vs genome-wide arrays (platform vs analysis)

Clinical Adoption in Australia:

- Available through a small number of providers - Major fetal structural abnormalities, replacement test whenpatient opts for invasive procedure, parental anxiety - Access to Medicare rebate + patient fee

Prenatal Microarrays

Illumina

How is this even possible?

Taken from Bianchi Nat Med 2012

New, Cutting Edge Technology

Ultrasound PracticesPublic Hospitals (Genetics)e.g. PathWest

Commercial Landscape

Medicare Funding for NIPT

- it is now on the agenda!

“Prospective, publicly-funded studies assessing the

cost-effectiveness of various screening strategies should

be performed as a matter of urgency”

While NIPT has lived up to many of its promises,

its appropriate integration with ultrasound (and

first trimester screening) is still evolving Hui et al, Ultrasound Obstet Gynecol. 2014 Oct 17.

BENEFITS OF NIPT

• Less women having invasive tests

• Test earlier in pregnancy

• No risk of miscarriage

• Detects the most common trisomies

• Higher detection sensitivity and lower false positive rates than MSS

LIMITATIONS

• NOT DIAGNOSTIC. IT IS ADVANCED SCREENING

• TEST FAILURE RATES (low fetal fractions)

• PPV (high risk results)

- Confirmatory testing needed

• False negatives do occur

MOVING TARGETS

• Total cost, out of pocket cost ($)

• TATs

• Australian laboratory provider (NATA accreditation)

• Medicare reimbursement

• Changing technology

• Broadening indications

THE NEXT WAVE

FUTURE DIRECTIONS

• Move to nth generational sequencing (NGS, single molecule seq.)

• Move to whole genome or genome/exome-wide analysis

• Greater complexity in terms of choices for patients, informed consent, result interpretation, pathology funding and clinical decision making

similar as for other applications of genomics but exacerbated due to time

constraints, parental anxiety, irreversible medical intervention

Thank You