evidence-based strategies for prenatal maternal screening

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GeneticScreeningWRAP. Evidence-Based Strategies for Prenatal Maternal Screening. Wayne W. Grody , MD, PhD Professor and Director Diagnostic Molecular Pathology Laboratory Department of Pediatrics and Human Genetics David Geffen School of Medicine at UCLA Los Angeles, California. - PowerPoint PPT Presentation


  • Evidence-Based Strategies for Prenatal Maternal Screening

    GeneticScreeningWRAPWayne W. Grody, MD, PhD Professor and Director Diagnostic Molecular Pathology Laboratory Department of Pediatrics and Human Genetics David Geffen School of Medicine at UCLA Los Angeles, California

  • Indications for Prenatal Diagnosis Maternal age

    Positive family history for a genetic disorder

    Presence of a chromosome abnormality in a parent

    Population screening; parent(s) found to be carrier of mutation

  • Grody, Annu. Rev. Med. 2003Disease Criteria for Population Genetic Risk ScreeningRelatively commonRelatively seriousManageable number of predominant mutationsHigh penetranceDefined and consistent natural historyEffective preventive or surveillance interventionsMutation detection relatively inexpensiveScreening test acceptable to populationInfrastructure in place for pre- and post-test education

  • Target ascertainment (age, ethnicity, etc.)Test offeringPre-test educationInformed consent (if applicable)Analytic phase (DNA test)Results interpretation and reportingPost-test counselingKey Components of the Genetic Risk Screening ProcessGrody, Annu. Rev. Med. 2003

  • Grody, Annu. Rev. Med. 2003Candidate Diseases for Inclusion in an Ashkenazi-Jewish Screening PanelDiseaseCarrier frequency in target populationTay-Sachs disease1/27Cystic fibrosis1/29Gaucher disease1/15Canavan disease1/36Familial dysautonomia1/30Connexin-26 deafness1/26Familial Mediterranean fever1/7Niemann-Pick disease, type A1/85Fanconi anemia, group C1/85Bloom syndrome1/100

  • Summary of ACMG Recommendations forPopulation-based Cystic Fibrosis Carrier ScreeningTesting should be offered to Caucasians and Ashkenazi Jews, and made available to all other ethnic groups.Either simultaneous or sequential couple screening may be used, as long as results are given to both partners.A universal, pan-ethnic core mutation panel should be used, consisting of: 25 mutations 3 exonic polymorphisms as reflex tests 5/7/9T intronic polymorphism as reflex test only if R117H is positiveGrody et al., Genet. Med. 2001

  • Summary of ACMG Recommendations forPopulation-based Cystic Fibrosis Carrier Screening

    Extended mutation panels for positive-negative couples should not be offered or encouraged.Reporting of results and residual risks should be based on the detection rates and model report forms developed by the committee.Primary care providers not comfortable with the complexities of these reports should refer the couple to a genetics professional. Quality assurance standards should adhere to the guidelines of ACMG, CAP, and the NIH-DOE Task Force on Genetic Testing.Grody et al., Genet. Med. 2001

  • F508 I507 G542X G551D W1282X N1303KR553X 621+1G>T R117H 1717-1G>A A455E R560TR1162X G85E R334W R347P 711+1G>T 1898+1G>A2184delA 1078delT* 3849+10kbC>T 2789+5G>A 3659delC I148T*3120+1G>AGrody et al., Genet. Med. 2001*Removed from panel in 2004 (Watson et al., Genet. Med. 2004)Recommended Core Mutation Panel forGeneral Population CF Carrier Screening

  • Nationwide CF Carrier Screening:Revelations from Post-market SurveillanceLow OB penetrationPanel mutation that is less frequent than expected: 1078delTPanel mutation that is not a mutation: I148TAdditional non-panel mutations that could qualify for inclusion: E60X, Q493X, S549N, 2183delAA>G, Y1092X, etc.Mutation screening panel inflation

  • Concerns About Expanded Mutation PanelsDeparts from endorsed standard of care (ACMG/ACOG)Added costFalse sense of securityArbitrary selection of low-frequency variantsUncertain allele frequency data for rare variantsWhy not just go directly to full sequencing?Paucity of genotype-phenotype correlation dataUnseemly competition: mutation arms racePotential for limited access or monopolizationLaw of diminishing returns: sensitivity claims belied by field experience thus farThe paradox of dwindling predictive valueSocial/religious/genetic considerations in ethnic targeting

  • Suboptimal test sensitivityEthnic differencesEducation and counselingAnxiety and stigmatizationInformed consentConfidentialityInsurabilityGenetic and clinical burdenAbortion Ethical Issues in Cystic Fibrosis Mutation Screening

  • Chromosome Disorders Are A Major Category of Genetic Disease

    Nearly 1% of live birthsApprox 2% of prenatal diagnoses in women >35 yrs old50% of all first trimester spontaneous abortions

  • What are the Indications for Ordering a Chromosome Analysis?Growth and developmental abnormalitiesFamily history of chromosome abnormalities

    Pregnancy with advanced maternal age (AMA)Stillbirth/neonatal deathInfertility/history of pregnancy lossNeoplasia

  • Maternal Serum Alpha-FetoproteinMSAFPIncreased with open neural tube defectTest at 16 weeksMoM = Multiple of the median

  • Triple Marker ScreenAFP, uE3, hCGScreens for NTD, Down syndrome, trisomy 18Tested at 15-20 weeksBased on MoMAFP and uE3 decreased in trisomieshCG increased in trisomy 21, decreased in trisomy 18

  • Triple Marker Screen Results

  • Risk of Down Syndrome by Maternal AgeMaternal AgeRisk20 1/1,667 1/1,000 1/500 1/106 1/3049 1/11

  • Fragile X Clinical Features>90% have mental retardation; IQ 0-60, mean 30-45In children, may present with: hyperactivity, ADD, autistic features, hyperextensible joints, mitral prolapseAfter puberty: macroorchidism, long face with large ears and prominent jaw

  • CGG Repeat in Fragile X SyndromeNormal range: 6-54 repeatsPremutation range: 52-200 repeatsFull mutation range: 200- >1000 repeatsAlleles with >200 repeats are hypermethylated, transcriptionally repressed

  • Length of Maternal PremutationIncidence of Full Mutation in OffspringNolin et al., Am. J. Hum. Genet. 1996


  • Is the Fragile X Premutation Really Asymptomatic?Recent reports of premature ovarian failure in female premutation carriersLate-onset tremor-ataxia-dementia syndrome in male premutation carriersMay be due to mRNA interference with expression of the normal FMR1allele or of other genes

  • Fetal Cells in Maternal BloodPresent in very small numbersRequires highly sensitive PCR and/or cell sortingBeware of long-lived fetal lymphocytes

  • GeneticScreeningWRAP


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