Advanced Obstetric Ultrasound Update

Prenatal Genetic Screening & Diagnosis

Katherine Rose Senior Genetic Counsellor

Monash Genetics

Presentation summary

Reproductive genetic carrier screening

Prenatal genetic screening

Prenatal genetic diagnosis

Chromosomes & Genes

Genetic conditions

• Genetic conditions account for 20% of infant deaths and 18% of paediatric hospitalisations 1.

• 1 out of 100 children world wide are born with a genetic condition 2.

• We all carry 4-5 recessive alleles for a serious condition 3.

1) Comprehensive carrier screening and molecular diagnostic testing of the for recessive childhood diseases Kingsmore S. Plos Currents. 2012 May; e4f98777ab8ffa9 2) Genes and human diseases World Health Organization – Genomic Resource Centre 3) An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Lazarin GA et al . Genetics in Medicine (2013) 15, 178–186

Reproductive Genetic Carrier Screening

Genetic testing designed to identify those with an increased chance of giving birth to a baby with a specific heritable condition.

• RANZCOG recommendations • Pre-pregnancy, or early pregnancy • Single conditions, limited panels, or next

generation extended panels • Recessive conditions (AR or X-linked) • Collectively conditions are not rare

Reproductive Genetic Carrier ScreeningTesting Lab Conditions Tested Approx Cost*

(AUD)

Cost for Partner Turn-around time

Invitae Comprehensive Carrier Screen

https://www.invitae.com/en/

CF, SMA, FRAX

Total 287 conditions

~$344

(USD $250)

~$138 (USD $100) if tested within 1 month.

(full panel)

10-21 days

VCGS Prepair Carrier Screen https://www.vcgs.org.au/tests/prepair

CF, SMA, FRAX

Total 3 conditions

$385 $220 per condition

$385 for 2 or 3

10 days

VCGS Expanded Carrier Screen https://www.vcgs.org.au/expandedcarrier

CF, SMA, FRAX >250 conditions Uses Invitae panel

~$900 VCGS fee Invitae fee

Cost is per couple, couple risk given only

21-28 days

Myriad Women’s Health (formerly Counsyl) The Myriad Foresight Carrier Screen

https://myriadwomenshealth.com/patient/foresight-carrier-screen/

CF, SMA, FRAX Total 176 Conditions

$579 $579 (full panel)

10-21 days

Virtus Diagnostics Preconception Genetic Screen

https://www.virtusdiagnostics.com.au/specialist-genetic-testing/preconception-genetic-screening/

CF, SMA, FRAX Total 590 conditions

$750

($1400 per couple upfront)

$750 (full panel)

14-21 days

Sonic Genetics Becon Expanded Carrier Screen

https://www.sonicgenetics.com.au/rcs/beacon/

CF,SMA, FRAX

Total >400(f) >350(m) conditions

$595 $595

(full panel)

5 weeks

• VCGS Pre and Early Pregnancy Genetic Counselling Clinic, Royal Children’s Hospital, Parkville, (03) 9936 6402. • Genetic Clinics Australia, 236 Glen Eira Road, Caulfield North, 9528-1910, www.geneticclinic.com.au Private Service • Eugene Labs https://eugenelabs.com/ Online service only.

Mackenzies Mission

Prenatal screening

Gestational stage Miscarriage risk Accuracy

Non invasive prenatal testing (NIPT) – cell free fetal DNA

10 weeks 0 ~ 99%

Combined first trimester screen (CFTS) - analytes & ultrasound measurements

12 weeks 0 ~ 90%

Second trimester maternal serum screening - analytes

14 - 20 weeks 0 75-80%

NIPT optionsTest Laboratory Screens for Details

Percept VCGS Pathology Common trisomies Rare aneuploidies and large CNVs Sex chromosome aneuploidies (SCA) fetal sex

~$449 Maternal blood sample from 10 weeks Results within 4-5 working days

NEST Monash IVF, Monash Ultrasound for Women

Illumina Common trisomies Sex chromosome aneuploidies (SCA) fetal sex

~$445 maternal blood sample from 10 weeks Results within 3-5 business days 0.1% test failure rate

Harmony

Women’s Ultrasound Melbourne

Sequenom Melbourne Pathology Australian Clinical Laboratories

Common trisomies Sex chromosome aneuploidies (SCA) and fetal sex (optional) +/- DiGeorge syndrome

~$430- $500 Maternal blood sample from 10 weeks Results within 7 working days <4% test failure rate

Generation Dorevitch Common trisomies Sex chromosome aneuploidies (SCA) fetal sex (optional) +/- Microdeletion panel (Generation Plus): DiGeorge syndrome, 1p36 Deletion syndrome Angelman syndrome, Prader-Willi syndrome Wolf-Hirschhorn syndrome, Cri-du-chat syndrome

~$395 Maternal blood sample from 10 weeks Results within 5-7 working days <0.1% test failure rate $695 (Generation Plus) Results within 7-12 working days

Panorama Melbourne IVF, Women’s Ultrasound Melbourne

Vistara

Natera Common trisomies Sex chromosome aneuploidies (SCA) fetal sex (optional) +/- Microdeletion panel: DiGeorge syndrome, 1p36 Deletion syndrome Angelman syndrome, Prader-Willi syndrome Cri-du-chat syndrome

Single gene (e.g. Noonan, achondroplasia)

~$450-$625 maternal blood sample + paternal sample from 9 weeks Results within 2-3 weeks <0.1% test failure rate

~$1350, results 3-4 weeks.

Combined First Trimester Screening (CFTS)

• Screens for T21, T18, T13, +/- pre-eclampsia • Does not detect neural tube defects • Blood test ~10 weeks

• Analytes: βHCG & PAPP-A • NT ultrasound ~12 weeks

• Measurements: CRL, NT +/- NB (accredited providers) • Combined results ~2 days after u/s report received by lab • Cut-offs for test offered by VCGS:

• T21: 1 in 300 T18: 1 in 175 T13: 1 in 100 • Private test, out of pocket cost • Sometimes an indicator for another abnormality

Second Trimester Maternal Serum Screening

• Screens for T21, T18, NTD • Blood test 14 - 20 weeks gestation

• Analytes: AFP, estriol, βHCG & inhibin-A • Results ~4 working days after blood received by lab • Cut-offs for test offered by VCGS:

• T21: 1 in 250 T18: 1 in 200 NTD: >2.5MoM AFP • May be an indicator for late pregnancy complications • Funded for public patients

Counselling aid: Standard

Counselling aid: AMA

Counselling aid: Increased Risk

Prenatal diagnosis

• Screening results are NOT definitive • Diagnostic testing is recommended

Gestational stage Miscarriage risk Accuracy

Chorionic Villus sampling (CVS) 11 - 13 weeks *0.2-1% 99.8%

Amniocentesis 15 – 18 weeks *0.1-0.5% 99.9%

*Akolekar et al (2015). Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound in Obstetrics and Gynecology. 45(1): 16-26.

Chromosome testing• FISH (Fluorescent Insitu Hybridisation)

• 1-2 days for results • Detects the most common aneuploidies (21, 13, 18, X, Y) • First tier test at Monash Health, funded for all patients

• Conventional “G-banded” karyotype • ~2 weeks for results • Detects all large chromosome anomalies (aneuploidies, partial

chromosome imbalances, balanced rearrangements) • Used to confirm abnormal FISH at Monash Health • Otherwise optional, out of pocket cost (except under certain

circumstances i.e translocations)

• Chromosome microarray (CMA) • ~2 weeks for results • Detects microdeletions / microduplications (CNVs), whole

chromosome aneuploidy (cannot detect balanced rearrangements) • 2%-20% higher yield than banded karyotype • Recommended for abnormalities on ultrasound • May detect variants of unknown/uncertain significance (VUS) • May detect unexpected findings • Optional at Monash Health, out of pocket cost (except under certain

circumstances i.e ultrasound abnormalities, FHx CNV)

CMA results

• Pathogenic variants, incl. unexpected findings • Variants of unknown/uncertain significance (VUS)

• associated with abnormal phenotype, but also observed in healthy control populations (uncertain), or

• not previously reported (unknown) • Benign variants (not reported)

• Interpretation of VUS • Parental samples – inherited or de novo? • Detailed family history • Sources of information: genome browsers, clinical/laboratory/

research databases, scientists • Deletion vs duplication • Size and gene content • Likely pathogenic vs likely benign? • May remain uncertain...........

PND for single gene disorders

• What is the condition? • Is patient at high risk? • Is there a genetic test available for PND? • Considerations for patients who present prior to mutation being known in family.

• Extensive work-up is required • Procedure booked in advance, labs notified, couriers organised,

funding negotiated, parental samples • Counselling about condition, test & possible results • Issues surrounding TOP explored • Consent & contract to obtain results

PND following detection of ultrasound abnormalities

• Appointment with Clinical Geneticist • Liaise with FDU/ antenatal doctors • Take detailed personal/ family history • Review the ultrasound findings • Determine likelihood of underlying genetic diagnosis • Explore possible prognosis • Is genetic testing available? • Explore options of:

• Termination of pregnancy • Recommendation of post-mortem, DNA storage • Genetics to review baby after delivery if ongoing pregnancy

• Early referrals are encouraged

Prenatal exomes

• Exome Technology: • Sequencing of the entire coding region of

the genome (~2%) in a single test • Allows analysis of many genes • High diagnostic yield in paediatric setting • 8.3M rare disease project, MSAC

approval for paediatric exomes

• Prenatal Exome: • Not there yet….but watch this space… • Stakeholder involvement needed • Carefully planned roll-out (specific

indications, tight gene lists, rapid testing, staff, funding)

• Clinical testing in research setting

Monash Genetics

General enquires/queries (P: 9594 2026)

Referrals welcome (F: 9594 6022, E: monashgenetics@monashhealth.org)

• Please include all relevant results • For reproductive counselling please include name & DOB of woman

and partner, where possible • Refer, or discuss with Geneticists, as early as possible