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Evidence-Based Strategies for Prenatal Maternal Screening

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.

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Evidence-Based Strategies for Prenatal Maternal Screening

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  1. GeneticScreeningWRAP Evidence-Based Strategies for Prenatal Maternal Screening Wayne W. Grody, MD, PhDProfessor and DirectorDiagnostic Molecular Pathology LaboratoryDepartment of Pediatrics and Human GeneticsDavid Geffen School of Medicine at UCLALos Angeles, California

  2. 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

  3. Disease Criteria for Population Genetic Risk Screening • Relatively common • Relatively serious • Manageable number of predominant mutations • High penetrance • Defined and consistent natural history • Effective preventive or surveillance interventions • Mutation detection relatively inexpensive • Screening test acceptable to population • Infrastructure in place for pre- and post-test education Grody, Annu. Rev. Med. 2003

  4. Key Components of the Genetic Risk Screening Process • Target ascertainment (age, ethnicity, etc.) • Test offering • Pre-test education • Informed consent (if applicable) • Analytic phase (DNA test) • Results interpretation and reporting • Post-test counseling Grody, Annu. Rev. Med. 2003

  5. Candidate Diseases for Inclusion in an Ashkenazi-Jewish Screening Panel Disease Carrier frequency in target population Tay-Sachs disease 1/27 Cystic fibrosis 1/29 Gaucher disease 1/15 Canavan disease 1/36 Familial dysautonomia 1/30 Connexin-26 deafness 1/26 Familial Mediterranean fever 1/7 Niemann-Pick disease, type A 1/85 Fanconi anemia, group C 1/85 Bloom syndrome 1/100 Grody, Annu. Rev. Med. 2003

  6. Summary of ACMG Recommendations forPopulation-based Cystic Fibrosis Carrier Screening • Testing 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 positive Grody et al., Genet. Med. 2001

  7. 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

  8. Recommended Core Mutation Panel for General Population CF Carrier Screening† F508 I507 G542X G551D W1282X N1303K R553X 621+1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711+1G>T 1898+1G>A 2184delA 1078delT* 3849+10kbC>T 2789+5G>A 3659delC I148T* 3120+1G>A †Grody et al., Genet. Med. 2001 *Removed from panel in 2004 (Watson et al., Genet. Med. 2004)

  9. Nationwide CF Carrier Screening:Revelations from “Post-market Surveillance” Low OB penetration Panel mutation that is less frequent than expected: 1078delT Panel mutation that is not a mutation: I148T Additional non-panel mutations that could qualify for inclusion: E60X, Q493X, S549N, 2183delAA>G, Y1092X, etc. Mutation screening panel “inflation”

  10. Concerns About Expanded Mutation Panels • Departs from endorsed standard of care (ACMG/ACOG) • Added cost • False sense of security • Arbitrary selection of low-frequency variants • Uncertain allele frequency data for rare variants • Why not just go directly to full sequencing? • Paucity of genotype-phenotype correlation data • Unseemly competition: “mutation arms race” • Potential for limited access or monopolization • Law of diminishing returns: sensitivity claims belied by field experience thus far • The paradox of dwindling predictive value • Social/religious/genetic considerations in ethnic targeting

  11. Ethical Issues in Cystic Fibrosis Mutation Screening • Suboptimal test sensitivity • Ethnic differences • Education and counseling • Anxiety and stigmatization • Informed consent • Confidentiality • Insurability • Genetic and clinical burden • Abortion

  12. Chromosome Disorders Are A Major Category of Genetic Disease • Nearly 1% of live births • Approx 2% of prenatal diagnoses in women >35 yrs old • 50% of all first trimester spontaneous abortions

  13. Growth and developmental abnormalities Family history of chromosome abnormalities Pregnancy with “advanced maternal age” (AMA) Stillbirth/neonatal death Infertility/history of pregnancy loss Neoplasia What are the Indications for Ordering a Chromosome Analysis?

  14. Maternal Serum Alpha-Fetoprotein • MSAFP • Increased with open neural tube defect • Test at 16 weeks • “MoM” = Multiple of the median

  15. Triple Marker Screen • AFP, uE3, hCG • Screens for NTD, Down syndrome, trisomy 18 • Tested at 15-20 weeks • Based on MoM • AFP and uE3 decreased in trisomies • hCG increased in trisomy 21, decreased in trisomy 18

  16. Triple Marker Screen Results

  17. Risk of Down Syndrome by Maternal Age • Maternal AgeRisk • 20 1/1,667 • 1/1,000 • 1/500 • 1/106 • 1/30 • 49 1/11

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

  19. CGG Repeat in Fragile X Syndrome • Normal range: 6-54 repeats • Premutation range: 52-200 repeats • Full mutation range: 200- >1000 repeats • Alleles with >200 repeats are hypermethylated, transcriptionally repressed

  20. Length of Maternal Premutation Incidence of Full Mutation in Offspring Nolin et al., Am. J. Hum. Genet. 1996

  21. Is the Fragile X PremutationReally Asymptomatic? • Recent reports of premature ovarian failure in female premutation carriers • Late-onset tremor-ataxia-dementia syndrome in male premutation carriers • May be due to mRNA interference with expression of the normal FMR1allele or of other genes

  22. Fetal Cells in Maternal Blood • Present in very small numbers • Requires highly sensitive PCR and/or cell sorting • Beware of long-lived fetal lymphocytes

  23. GeneticScreeningWRAP

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