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  • 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

    http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://currents.plos.org/genomictests/article/comprehensive-carrier-screening-and-molecular-diagnostic-testing-for-recessive-childhood-diseases/ http://www.who.int/genomics/public/geneticdiseases/en/index2.html https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908551/

  • 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 Screening Testing 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.

    https://www.invitae.com/en/ https://www.vcgs.org.au/tests/prepair https://www.vcgs.org.au/tests/prepair https://www.vcgs.org.au/expandedcarrier https://myriadwomenshealth.com/patient/foresight-carrier-screen/ https://www.virtusdiagnostics.com.au/specialist-genetic-testing/preconception-genetic-screening/ https://www.sonicgenetics.com.au/rcs/beacon/ http://www.geneticclinic.com.au/ https://eugenelabs.com/

  • 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 options Test 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

  • 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 • Likel

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