in the Prenatal and Preconception Settings

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					Cystic Fibrosis
  SCREENING
 in the Prenatal and Preconception Settings

SCHEDULE OF 60 MINUTE CME TELECONFERENCES
Tuesday, March 30, 2004                            12:00 PM EST
Wednesday, March 31, 2004                           3:00 PM EST
Monday, April 5, 2004                               5:00 PM EST
Wednesday, April 7, 2004                            8:00 PM EST
Thursday, April 8, 2004                             2:00 PM EST

Introduction, Greetings, Disclosures, and Acknowledgements

Development, Molecular Genetics, and Initial Experience of the CF
Screening Guidelines
Wayne W. Grody MD, PhD
Practical Suggestions for Implementing CF Screening
Joe Leigh Simpson, MD
Questions and Answers


INSTRUCTIONS FOR THE TELECONFERENCE
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• In the event you are called or beeped during the discussion, please hang up and make your call. When
  you are ready to be reconnected, call the conference operator at 1-877-465-1386 specified by the
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  please press *0 on your telephone keypad.




       Sponsored by Medical Education Group LLC




          Supported by an unrestricted educational grant from Quest Diagnostics Incorporated.
Cystic Fibrosis
  SCREENING
in the Prenatal and Preconception Settings

OVERVIEW
In April 1997, the National Institute of Health (NIH) Consensus Development Conference on Genetic
Testing for Cystic Fibrosis recommended that genetic carrier screening for CF mutation should be
offered to adults with a family history of CF, to partners of people with CF, to couples currently planning
a pregnancy, and to couples seeking prenatal care. This was followed in October 2001 by similar recom-
mendation from the American College of Obstetricians and Gynecologists (ACOG) and the American
College of Medical Genetics (ACMG).

In December 2001, ACOG issued a news release that modified who should be tested. In the news release
it was indicated that physicians should "recommend" CF testing to Caucasians and Ashkenazi Jews, and
at least "make available" CF screening to all other ethnicities. This broadened the potential audience to
most Americans.

Cystic fibrosis was the first genetic test that received a recommendation for widespread screening. In
addition, the interpretation of test results can often prove difficult. Together, this has led to the need for
widespread education of obstetricians and gynecologists.


TARGET AUDIENCE
This CME activity will be beneficial for physicians providing obstetrical and gynecological care,
nurse-midwives, and other professionals who treat preconception, infertility, and obstetrics patients.


LEARNING OBJECTIVES
At the conclusion of this CME activity, participants should be able to:
  • Identify the history and discuss ACOG/ACMG recommendations for CF testing
  • Identify the laboratory and clinical issues involved in CF testing
  • Explain the applications of couple versus sequential screening models
  • Restate the term "polymorphism"
  • Recite genetic screening guidelines and issues related to CF
  • Identify counseling issues and patient education methods for presenting infertility test results.


ACCREDITATION STATEMENT
Medical Education Group LLC is accredited by the Accreditation Council for Continuing Medical
Education to sponsor continuing medical education for physicians.

CREDIT DESIGNATION
Medical Education Group LLC designates this educational activity for a maximum of 1.0 category
1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits
he/she actually spent in the educational activity.
FACULTY
Wayne W. Grody, MD, PhD
Professor, Divisions of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics
Director, Diagnostic Molecular Pathology Laboratory
UCLA School of Medicine, California


Joe Leigh Simpson, MD
Chairman and Professor, Department of Obstetrics & Gynecology
Professor Department of Molecular and Human Genetics
Baylor College of Medicine, Texas


DISCLOSURE DECLARATION
It is the policy of Medical Education Group LLC to ensure balance, independence, objectivity and
scientific rigor in all continuing medical education activities. Faculty members participating in an activity
are required to disclose to the audience any relationship they may have with the commercial supporter of
the activity or with any other commercial company whose products or devices may be mentioned in the
presentations.

DISCLOSURES
Dr. Grody serves on the Advisory Board for Roche Molecular Biochemicals. Dr. Simpson has no
significant financial interest in or other relationship with the manufacturer of any of the products or
devices of any of the services that he intends to discuss.

UNLABELED/INVESTIGATIONAL USE DISCLOSURES
During the presentation, faculty members may include a discussion of an unlabeled or investigational use
not approved for commercial product. Each faculty member is required to disclose this information to the
audience when referring to an unlabeled or investigational use.

The presentations of Dr. Grody and Dr. Simpson will not include discussion of off-label investigational
use of pharmaceutical products or medical devices.

DISCLAIMER
The faculty members, Medical Education Group LLC and Quest Diagnostics Incorporated do not
recommend the use of any pharmaceutical, diagnostic test, or device outside of the labeled indications
approved by the FDA. Please refer to the official prescribing information for each product for approved
indications, contraindications and warnings.
Any procedures, medications, devices, or other courses of diagnosis or treatment discussed or suggested
in this CME activity should not be used by clinicians without evaluation of their patients’ conditions and
possible contraindications or dangers of use. It is recommended that physicians review any applicable
manufacturer’s product information and compare any off-label discussions with other authorities.

FEE
There is no fee for this CME activity. To obtain a Certificate of Completion for this activity, participants
must complete the CME Credit Form and Evaluation Form located in the back of this syllabus or visit
www.megcme.com to apply online.
Cystic Fibrosis
  SCREENING
in the Prenatal and Preconception Settings




Development, Molecular Genetics, and
Initial Experience of the CF Screening
Guidelines
  Wayne W. Grody, MD, PhD
  Professor, Divisions of Pathology and Laboratory Medicine, Pediatrics, and
  Human Genetics
  Director, Diagnostic Molecular Pathology Laboratory
  UCLA School of Medicine, California


  BIOGRAPHICAL SKETCH
  Dr. Wayne W. Grody is a professor in the Divisions of Medical Genetics and Molecular Pathology at the
  University of California Los Angeles (UCLA) School of Medicine and director of the Diagnostic
  Molecular Pathology Laboratory at the UCLA Medical Center. He is also an attending physician in the
  Department of Pediatrics at UCLA Medical Center, specializing in the care of patients with, or at risk
  for, genetic disorders. Dr. Grody is heavily involved in basic molecular genetics research and
  instruction. He has helped develop quality assurance and ethical guidelines for DNA-based genetic
  testing for a number of governmental and professional agencies. Recently, he chaired 2 American
  College of Medical Genetics (ACMG) working groups that were developing screening
  recommendations for cystic fibrosis and factor V-Leiden mutation. Dr. Grody completed his
  undergraduate work at Johns Hopkins University in Baltimore, Maryland, received his MD and PhD
  degrees at Baylor College of Medicine in Houston, Texas, and completed residency and fellowships
  training at UCLA. He is board certified by the American Board of Medical Genetics and the American
  Board of Pathology.
       Development, Molecular
       Genetics, and Initial
       Experience of the CF
       Screening Guidelines

       Wayne W. Grody, MD, PhD
       Professor, Divisions of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics
       Director, Diagnostic Molecular Pathology Laboratory
       UCLA School of Medicine, California




                                                                                                   1




Areas of Application of
Molecular Diagnostics

• Infectious disease
• Neoplastic disease
• Genetic disease
• Identity testing




                                                                                                   2




Areas of Molecular Genetic
Testing

• Clinical diagnosis/confirmation
• Carrier screening
• Newborn screening
• Prenatal diagnosis
• Presymptomatic/predisposition
diagnosis

                                                                                                   3
Molecular Classification of
Genetic Disease

• Disorders for which both the gene
and mutation are known
• Disorders for which the gene is
known, but not the mutation
• Disorders for which neither the gene
  nor the mutation is known
• Polygenic disorders                    4




Cystic Fibrosis:
Clinical Features

• Disorders for which both the gene
and mutation are known
• Disorders for which the gene is
known, but not the mutation
• Disorders for which neither the gene
  nor the mutation is known
• Polygenic disorders                    5




Laboratory Diagnosis and
Screening of Cystic Fibrosis

• Sweat testing
• Immunoreactive trypsin test (IRT)
• DNA analysis




                                         6
           Treatment of Cystic Fibrosis

           •       Pulmonary therapy
                   -   antibiotics
                   -   bronchodilators
                   -   mucolytics
                   -   chest PT
                   -   lung transplantation

           •       Digestive therapy
                   - pancreatic enzyme replacement
                   - dietary supplements

           •       Reproductive therapy
                   - genetic counseling
                   - sperm aspiration and ICSI

           •       Gene therapy?                                                            7




           Inheritance of Cystic Fibrosis




                                                                                            8
U.S.Congress, Office of Technology Assessment, Washington DC, 1992




           Cystic Fibrosis Carrier
           Frequencies in Various American
           Ethnic/Racial Populations

           European Caucasian                                                 1/29
           Ashkenazi Jewish                                                   1/29
           Hispanic American                                                  1/46
           African American                                                   1/65
           Asian American                                                     1/90


ACOG/ACMG, Preconception and prenatal carrier screening for cystic fibrosis: Clinical and   9
laboratory guidelines. Washington DC, 2001
            The Cystic Fibrosis Gene:
            Vital Statistics
             • Complete gene locus spans 250 kb1
             • 27 exons1
             • Mature mRNA of 6,500 bases2
             • Encodes an ion channel of 1,480
             amino acids (CFTR)2
             • Three-nucleotide deletion of codon
             508 (phe) in 70%3
1
    Rommens JM, Iannuzzi MC, Kerem B et al. Science. 1989;245:1059-65.
2   Riordan JR, Rommens JM, Kerem B et al. Science. 1989;245:1066-1073.    10
3
    Kerem B, Rommens JM, Buchanan JA et al. Science. 1989;245:1073-1080.




                                         F508

                                                                           11




            Distribution of Cystic Fibrosis
            Mutations




                                                                           12
National Center for Humane Genome
Research (NCHGR) Cystic Fibrosis
Screening Consortium

Site                                             Principal Investigator
UCLA                                             W. Grody
Johns Hopkins                                    N. Holtzman
Univ. of Rochester                               P. Rowley
Vanderbilt                                       J. Phillips
Univ. of Pennsylvania                            D. Asch
Univ. of North Carolina                          J. Sorenson
California Pacific                               J. Fanos
 Medical Center

                                                                                13




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                                                                      14




         High Frequency of the
         R117H Cystic Fibrosis
         Mutation in Patients
         With Congenital
         Absence of the Vas
         Deferens




          Gervais R, Dumur V, Rigot JM et al. N Engl J Med. 1993;328:446-447.   15
          NIH Consensus Development
          Conference

          NIH Consensus Development Conference
          GENETIC TESTING FOR CYSTIC
          FIBROSIS
          Bethesda, April 14-16, 1997
          “...recommended that testing for gene
          mutations that cause cystic fibrosis be
          offered as an option to all pregnant couples
          and those planning pregnancy.”

 NIH Consensus Development Conference. Arch Intern Med. 1999;159:1529-1539.        16




          Steering Committee

          Charge: To develop clinical and laboratory provider
          guidelines for population-based cystic fibrosis
                      carrier screening

          Sponsoring Organizations:
                           ACMG
                           ACOG
                           NHGRI
          Working Groups:
                           1. Provider education
                           2. Laboratory testing, interpretation, and counseling
                           3. Patient education and informed consent

                                                                                   17




          Summary of ACMG Recommendations
          for Population-based Cystic Fibrosis
          Carrier Screening

          • Testing should be offered to Caucasians and Ashkenazi
             Jews and made available to all other ethnic groups.
          2. Either simultaneous or sequential couple screening may be
             used, as long as results are given to both partners.
          3. 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 WW, Cutting GR, Klinger KW, et al. Genet Med. 2001;3:149-154.
                                                                                   18
          Summary of ACMG Recommendations
          for Population-based Cystic Fibrosis
          Carrier Screening (continued)

          4. Extended mutation panels for positive-negative couples should not
              be offered or encouraged.

          5. Reporting of results and residual risks should be based on the
              detection rates and model report forms developed by the
              committee.

          6. Primary care providers not comfortable with the complexities of
               these reports should refer the couple to a genetics professional.

          7. Quality assurance standards should adhere to the guidelines of
              ACMG, CAP, and the NIH-DOE Task Force on Genetic Testing.




Grody WW, Cutting GR, Klinger KW, et al. Genet Med. 2001;3:149-154.
                                                                                                 19




          Recommended Core Mutation Panel
          for General Population CF Carrier
          Screening

          Standard Mutation Panel
            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




                                                                                                 20
Grody WW, Cutting GR, Klinger KW, et al. Genet Med. 2001;3:149-154.




          ASR Platforms For Cystic
          Fibrosis Mutation Testing

          • Reverse dot blots (Roche, Innogenetics)
          • Amplification refractory mutation detection
          system (ARMS) (Orchid)
          • Oligonucleotide ligation assay (OLA)
          (Abbott/Celera)
          • Oligonucleotide microarray (Nanogen,
          Autogenomics, BioArray Solutions)
          • Invader assay (Third Wave)
                                                                                                 21
          Linear Array CF Gold
          (example)




                                                                                   22




          The Intronic 5T/7T/9T
          Polymorphism in the CFTR Gene

           • R117H + 5T in cis   CF1
           • R117H + 7T in cis   CBAVD1,2
           • R117H + 5T in trans  CBAVD2
           • 5T/5T homozygosity    CBAVD2

              - R117H only associated with CF when same allele
                contains 5T (cis)1
              - 5T confers lowest RNA splicing efficiency3
              - 5T carried in 5% of US population3

1
    Kiesewetter S, Macek M Jr, Davis C, et al. Nat Genet. 1993;5:274-278.
2   Chillon M, Casals T, Mercier B, et al. N Eng J Med. 1995;332:1475-1480.        23
3
    Friedman KJ, Heim RA, Knowles MR, Silverman LM. Hum Mutat. 1997; 10:108-115.




                                                                                   24
                                                                    25




          Nationwide CF Carrier Screening:
          Revelations From “Post-market
          Surveillance”

          • Panel mutation that is less frequent than expected:
            1078delT
          • Panel mutation that is not a mutation: I148T
          • Additional relevant variant affecting expression of a
            panel mutation: 3199del6
          • Additional non-panel mutations that could qualify for
            inclusion: E60X, Q493X, S549N, 2183delAA>G,
            Y1092X
          • Low OB penetration
          • Improper ordering/reporting of 5T polymorphism
                                                                    26




          The Kaiser Experience

          • 50,000 patients screened

          • 1,776 carriers detected (1/28)

          • 50 at-risk couples, 63 pregnancies

          • Incidence of CF in population
            reduced by 50%


                                                                    27
Witt D, Wold C, Louie E, Goonewardena P. ASHG 2003, Abstract 255.
Potential Targets of Mass
Population Molecular Genetic
Screening Programs
• Cystic fibrosis
• Thrombophilia panel
   – factor V-Leiden
   – prothrombin 20210A variant
   – protein S deficiency
   – protein C deficiency
   – methylenetetrahydrofolate reductase variant
   – angiotensin converting enzyme polymorphism
• Hemochromatosis
• Alzheimer’s disease (ApoE4 allele)
• HIV resistance (CKR-5 deletion)
• Age-related macular degeneration
• Fragile X syndrome
• Congenital deafness (connexin-26)                28
Development, Molecular Genetics, and Initial Experience of the
CF Screening Guidelines
Wayne W. Grody, MD, PhD



  REFERENCE LIST
  American College of Obstetricians and Gynecologists/American College of Medical Genetics.
  Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines.
  Washington, DC: American College of Obstetricians and Genetics; 2001.

  Chillón M, Gasals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital
  absence of the vas differens. N Engl J Med. 1995; 332:1475-1480.

  Friedman KJ, Heim RA, Knowles MR, Silverman LM. Rapid characterization of the variable length
  polythymidine tract in the cystic fibrosis (CFTR) gene: association of the 5T allele with selected CFTR
  mutations and its incidence in atypical sinopulmonary disease. Hum Mutat. 1997; 10:108-115.

  Gervais R, Dumur V, Rigot J-M, Lafitte J-J, Roussel P. High frequency of the R117H cystic fibrosis
  mutation in patients with congenital absence of the vas deferens. N Engl J Med. 1993; 328:446-447.

  Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based
  cystic fibrosis carrier screening. Gent Med. 2001; 3:149-154.

  Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis.
  Science. 1989; 245:1073-1080.

  Kieswetter S, Macek, M Jr, Davis C, et al. A mutation in CFTR produces different phenotypes
  depending on chromosomal background. Nat Genet. 1993; 5:274-278.

  NIH Consensus Development Conference. Genetic testing for cystic fibrosis. Arch Intern Med. 1999;
  159:1529-1539.

  Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and
  characterization of complementary DNA. Science. 1989; 245:1066-1072.

  Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome
  walking and jumping. Science. 1989; 245:1059-1065.

  US Office of Technology Assessment. Cystic Fibrosis and DNA Tests: Implications of Carrier Screening.
  Washington, DC: US Government Printing Office; 1992.

  Witt D, Wold C, Louie E, Goonewardena P. Cystic fibrosis prenatal screening of over 50,000 members
  in a large HMO. Program update with an emphasis on the outcomes of high-risk pregnancies, reduction
  in the incidence of CF, and clinical utility. Abstract presented at: Annual Meeting of the American
  Society of Human Genetics; November 8, 2003; Los Angeles, Calf.
Cystic Fibrosis
  SCREENING
in the Prenatal and Preconception Settings




Practical Suggestions for
Implementing CF Screening
  Joe Leigh Simpson, MD
  Chairman and Professor, Department of Obstetrics & Gynecology
  Professor, Department of Molecular and Human Genetics
  Baylor College of Medicine, Texas


  BIOGRAPHICAL SKETCH
  Dr. Joe Leigh Simpson received his Doctor of Medicine degree from Duke University in Durham,
  North Carolina, and completed his residency training in obstetrics/gynecology and genetics at New
  York Hospital, Cornell University Medical College, in New York, New York. He is currently Chairman
  and Professor of Obstetrics and Gynecology and Professor, Department of Molecular and Human
  Genetics, at Baylor College of Medicine in Houston, Texas. Dr. Simpson also currently serves as
  treasurer of the American College of Medical Genetics (ACMG). A major contributor to the body of
  women’s health literature, Dr. Simpson has published more than 500 scientific articles in the areas of
  gynecology, obstetrics, and genetics. He is a member and office of numerous scientific and
  medical societies.
                          Practical Suggestions
                          for Implementing CF
                          Screening

                          Joe Leigh Simpson, MD
                          Chairman and Professor, Department of Obstetrics & Gynecology
                          Professor, Department of Molecular and Human Genetics
                          Baylor College of Medicine, Texas




                                                                                          1




          Prerequisites for Genetic
          Screening

          • Prenatal: Ability to identify matings between two
            heterozygotes
          • Postnatal: Capacity to alter clinical management
            of affected individuals
          • Cost-effectiveness
          • Reliable methods of assessing genetic status
            (reproducible assay)
          • Capacity to handle ancillary problems:
                  - variants not requiring action
                  - potential stigmatization of heterozygote

                                                                                          2




          Ethnic Background

          Black:     Sickle cell disease
          *Jewish: Tay-Sachs disease
                     Canavan disease
          Italian and Greek: -thalassemia
          Asian: -thalassemia


* Ashkenazi panel with other disorders available, but not standard per ACOG.              3
             Heterozygote Testing: Gene
             Product (Protein)

             Disorder                                        Test
             Tay-Sachs Disease                               Enzymatic testing
                                                             (Hex A/Hex B ratio)
             Sickle Cell Anemia                              Sickling phenomenon in
                                                             blood; hemoglobin
                                                             electrophoresis
               -thalassemia and                              Mean corpuscular
               -thalassemia                                  volume < 80%; hemoglobin
                                                             electrophoresis

                                                                                                4




             Cystic Fibrosis: Transmembrane
             Receptor (CFTR)
             • 1989 – Responsible gene (chloride channel)
               identified1,2
             • 1990s – Discussions on desirability of
               genetic screening; pilot studies
             • 1997 – NIH Workshop: genetic counseling should be
               offered to all couples seeking prenatal care3
             • 2001 – ACOG/American College of Medical Genetics
               (ACMG) guidelines with refined ethnic-specific
               recommendations and identification of panel of 25
               most common mutations (0.1% frequency or greater in
               general population)4

1   Rommens JM, Iannuzzi MC, Kerem B et al. Science. 1989;245:1059-65.
2
    Riordan JR, Rommens JM, Kerem B et al. Science. 1989;245:1066-1073.
3
    NIH Consensus Development Conference. Arch Intern Med. 1999;159:1529-1539.
4
    ACOG/ACMG, Preconception and prenatal carrier screening for cystic fibrosis: Clinical and   5
    laboratory guidelines. Washington DC, 2001.




             Positive Family History for
             Cystic Fibrosis (CF)

             • Normal parents with affected child (pulmonary and
               pancreatic disease) at risk for subsequent affected children
               (25%)
             • Affected patient (or spouse) at risk for affected fetus if
               partner is heterozygous (50%)
             • Clinically normal patient and spouse, one of whom has
               affected sibling. A normal sibling of an affected case has
               2/3 likelihood of heterozygosity; thus, fetus is at risk
             • Congenital bilateral absence of the vas deferens (CBAVD)
               in male partner (could be heterozygous for severe CFTR
               allele)

                                                                                                6
            Negative Family History:
            Applicable ACOG/ACMG CF
            Guidelines (2001)

            •     Caucasians of European or Ashkenazi Jewish
                  descent – “CF carrier screening should be
                  offered…”

            •     Other ethnic groups (African Americans,
                  Hispanic Americans, Asian Americans) – “CF
                  screening should be made available…”.
                  Assumes “no known ancestors from higher risk
                  groups” and no affected relatives


   ACOG/ACMG, Preconception and prenatal carrier screening for cystic fibrosis:                   7
   Clinical and laboratory guidelines. Washington DC, 2001




            CF Heterozygote Frequency and
            Detection Rates by Ethnic Group
                                                                                  Predicted Risk of
                                                                                  Heterozygosity
                                 Heterozygote             Detection               Despite Negative
                                 Frequency                 Rate                       Testing
Screening
“should be offered”
Ashkenazi Jewish                    1/29                      97%                      1/930
European Caucasian                  1/29                      80%                      1/140
Screening “should be
made available”
Hispanic Americans                  1/46                      57%                      1/105
African Americans                   1/65                      69%                      1/207
Asian Americans                     1/90                      N/A                      N/A


   ACOG/ACMG, Preconception and prenatal carrier screening for cystic fibrosis:
                                                                                                  8
   Clinical and laboratory guidelines. Washington DC, 2001




            Logistics of Screening the
            Clinically Normal Couple

            • Ideally screen before pregnancy, but at least at first
              prenatal visit

            • Provide ACOG Brochure Cystic Fibrosis Carrier
              Testing: The Decision Is Yours

            • Either state that providing brochure is mode of
              practice, or write note on every patient
            • Other educational aids available
              (e.g., videos, booklets)

                                                                                                  9
    Counseling Points
    •   Purpose of screening; voluntary nature
    •   Range of symptoms and severity of CF,
        treatment, life expectancy
    •   Genetics of CF (significance of autosomal
        recessive inheritance)
    •   Carrier risks in specific ethnic or racial groups
    •   Meaning of positive and negative CF screening
        results
    •   Factors to consider in deciding whether to
        undergo screening
                                                            10




    Limitations and Pitfalls of
    Cystic Fibrosis Screening

    •   Correct paternity assumed; results
        applicable only for current reproductive
        partners
    •   Assumption of negative family history
    •   Cannot detect all CF mutations
    •   Molecular heterogeneity may preclude
        predicting disease severity in affected
        offspring
                                                            11




    Screening Strategies
Concurrent: Both partners screened simultaneously.
Couple informed of results of both partners.

Pro •   Preferred or essential if time constraints exist
    •   Identifies each parent’s status for both present
        and future pregnancies with any partner
    •   Permits identification of other relatives at risk

Con •   Will generate unnecessary anxiety when one
        partner is a carrier and the other does not have
        a detectable mutation

                                                            12
        Screening Strategies (cont)
 Sequential: Second partner screened only if first is positive.
 Performed de facto if one partner is not available.

 Pro •          More efficient in ethnic groups having lower
                heterozygote frequencies
         •      Less anxiety, given no disclosure in +/- matings

 Con •          Residual risk higher than if both partners were
                negative
         •      Lack of full disclosure could prove arguable if
                reproductive partner changes
         •      No ability to identify relatives who also could be
                heterozygous                                                                13




        Risk of Cystic Fibrosis Fetus:
        Concurrent Versus Sequential
        Screening
                                                            Ethnic Origin
CF Status of Partners                                 European      Ashkenazi
No testing                                            1/3,300       1/3,300
            Concurrent
One positive; one negative                             1/560                  1/3,720
Both negative                                          1/78,400               1/3,459,600
             Sequential
One positive; one untested                             1/116                  1/116
One negative; one untested                             1/16,240               1/107,880


 ACOG/ACMG, Preconception and prenatal carrier screening for cystic fibrosis: Clinical      14
 and laboratory guidelines. Washington DC, 2001




        Utilization of Cystic Fibrosis
        Screening in U.S.

         •      Since 2001: Ten-fold increase in
                screening at one national referral lab

         •      Overall, estimated 800,000 to 1,000,000
                patients/year (20-25% all pregnancies
                in U.S.)



 Strom C. Symposium Presented at: ACMG Annual Genetics Meeting. Orlando, FL; 2004.          15
           Does Experience Match
           Expectations?
            •      California Kaiser Permamente offered
                   screening if one partner was of Caucasian
                   ancestry
            •      Cystic Fibrosis Panel of 37 mutations; reflex
                   poly T testing
            •      Of 50,000 screened, 1,776 heterozygotes
                   (1:28)
            •      CF incidence reduced by 50%
            •      Redistribution of health care resources from
                   direct care to preventive care
                                                                              16
    Witt D, Wold C, Louie E, Goonewardena P. ASHG 2003, Abstract 255.




           Problems Identified in
           Implementation
            •      Difficulty in stratifying by ethnic groups
            •      Confusion over whether 5T should be sought:
                   -    For classical CF screening: NO, except in
                        presence of R117H (reflex testing),
                   -    For CBAVD: YES, if requested for male
                        infertility evaluation
            •      Confusion over use of extended panels
                   (>23 mutations)
            •      Documentation and communication
            •      Uncertainty concerning when to refer to
                   geneticists
                                                                              17




           Clinical Correlates of 5T
            •      R117H and 5T on same chromosome (cis):
                   Associated with classical CF (pulmonary and
                   pancreatic disease)1
            •      Classical CF allele (e.g., F508) on one
                   chromosome with 5T on homologous chromosome
                   (trans): Associated with CBAVD2 but not
                   pulmonary or pancreatic disease
            •      Reasonable to assume any CBAVD case results
                   from two dysfunctional CF alleles, even if both
                   mutations not demonstrated or 5T present in
                   absence of demonstrable trans mutation
1   Kiesewetter S, Macek M Jr, Davis C, et al. Nat Genet. 1993;5:274-278.
2
                                                                              18
    Chillon M, Casals T, Mercier B, et al. N Eng J Med. 1995;332:1475-1480.
    Are Panels With More Than 23
    Mutations Necessary?

    •   Extended panels (>23 mutations):
        - Recommended in testing affected
        children
        - In absence of family history, not required
    •   Ethnic specific panels:
        - Uncertain utility
But •   Acceptable to use extended panels:
        - If offered, state nature of extended test
           and limitations
        - Screen every patient same way or
        devise system
        - Mention sequencing entire CFTR gene
                                                       19




    Easing Logistics Through
    Sample Letters (ACOG/ACMG)

    Prospective Parents
    •   Both partners tested and both negative
    •   One partner positive, one negative
    •   One partner positive, one not tested
    •   One partner negative, one not tested

    Relatives
    • Family members of patient identified as
      being carrier, placing other relatives at risk

                                                       20




    When is Genetic Referral Not
    Necessary?

    • Prior to initial screening in context of
      negative family history

    • If only a single partner proves
      heterozygous




                                                       21
When is Genetic Referral
Necessary?

• If both partners are heterozygous
  (positive screening)
• Discuss reproductive options (CVS,
  amniocentesis), diagnostic pitfalls,
  potential for heterozygosity in other
  family members
• Provide ACOG brochure What
  Happens If Both My Partner and
  I Are Carriers?                         22
Practical Suggestions for Implementing CF Screening
Joe Leigh Simpson, MD



   REFERENCE LIST
   American College of Obstetricians and Gynecologists/American College of Medical Genetics.
   Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines.
   Washington, DC: American College of Obstetricians and Genetics; 2001.

   Chillón M, Gasals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital
   absence of the vas differens. N Engl J Med. 1995; 332:1475-1480.

   Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis.
   Science. 1989; 245:1073-1080.

   Kieswetter S, Macek, M Jr, Davis C, et al. A mutation in CFTR produces different phenotypes
   depending on chromosomal background. Nat Genet. 1993; 5:274-278.

   NIH Consensus Development Conference. Genetic testing for cystic fibrosis. Arch Intern Med. 1999;
   159:1529-1539.

   Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and
   characterization of complementary DNA. Science. 1989; 245:1066-1072.

   Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome
   walking and jumping. Science. 1989; 245:1059-1065.

   Strom C. Laboratory implementation of CFTR mutation detection. Symposium presented at: Annual
   Clinical Genetics Meetings of the American College of Medical Genetics; March 4, 2004; Orlando, Fl.

   Witt D, Wold C, Louie E, Goonewardena P. Cystic fibrosis prenatal screening of over 50,000 members
   in a large HMO. Program update with an emphasis on the outcomes of high-risk pregnancies, reduction
   in the incidence of CF, and clinical utility. Abstract presented at: Annual Meeting of the American
   Society of Human Genetics; November 8, 2003; Los Angeles, Calf.
Cystic Fibrosis
  SCREENING
in the Prenatal and Preconception Settings

CME CREDIT FORM
Please apply for credit within 30 days of the final session. To receive credit, go to www.megcme.com and click on "Credit Form" for
the Cystic Fibrosis Screening program. By confirming your participation on-line, earned credits and program information will be
tracked automatically and will be readily accessible for review and printing. If you do not have Internet access, please complete this
form and the Evaluation Form and submit them via mail or fax to receive your Certificate of Completion in the mail within 6 weeks of
the last teleconference.

Please check the session in which you participated:
   Tuesday, March 30, 2004           12:00 PM EST                       Wednesday, April 7, 2004            8:00 PM EST
   Wednesday, March 31, 2004          3:00 PM EST                       Thursday, April 8, 2004             2:00 PM EST
   Monday, April 5, 2004              5:00 PM EST

I attest to having participated in Cystic Fibrosis Screening in the Prenatal and Preconception Settings and claim the following AMA
category 1 credit:
     1.0 hour               Signature

PLEASE PRINT

First Name                                                          Last Name

Degree                                       Specialty

Office/Lab/Hospital Affiliation

Mailing Address        Home       Office/Lab/Hospital


Department

City                                               State                                         Zip Code

Phone                                                      Fax

Email

Social Security Number or AMA Medical Education Number
(For record keeping only)

Please use a separate form for each person requesting credit; photocopies are acceptable.
MAIL FORM TO:                              OR FAX TO:
Cystic Fibrosis Screening                  (215) 244-0440
CME Program #038-206646
Medical Education Group LLC
7 Neshaminy Interplex, Suite 215
Trevose, PA 19053
EVALUATION FORM
Please evaluate the following program elements using this scale:
1= Poor, 2= Fair, 3= Good, 4= Very Good, 5= Excellent

1. WERE THE FOLLOWING LEARNING OBJECTIVES ACHIEVED?
    Please rate your ability to:
    a) Identify the history and discuss ACOG/ACMG recommendations for CF testing 1                                2         3         4          5

    b) Identify the laboratory and clinical issues involved in CF testing                                 1       2         3         4          5

    c) Explain the applications of couple versus sequential screening models                              1       2         3         4          5

    d) Restate the term "polymorphism"                                                                    1       2         3         4          5

    e) Recite genetic screening guidelines and issues related to CF                                       1       2         3         4          5

    f) Identify counseling issues and patient education methods for presenting infertility test results   1       2         3         4          5

2. PLEASE EVALUATE THE FACULTY FOR THIS ACTIVITY REGARDING PRESENTATION SKILLS AND EXPERTISE IN
   THEIR SUBJECT AREA:
    Wayne W. Grody, MD, PhD - Development, Molecular Genetics and Initial Experiences of CF Screeing Guidelines
    Presentation skills
    1 2 3 4 5                  Comment:
    Expertise in the subject area
    1 2 3 4 5                               Comment:

    Joe Leigh Simpson, MD - Practical Suggestions for Implementing CF Screening
    Presentation skills
    1 2 3 4 5                   Comment:
    Expertise in the subject area
    1 2 3 4 5                               Comment:

3. DID YOU FIND THE PRESENTATIONS BIASED IN REGARD TO THE COMMERCIAL SUPPORTER,
   QUEST DIAGNOSTICS INCORPORATED?
    YES      NO        If yes, please explain:


4. DO YOU THINK THAT YOU WILL CHANGE YOUR PRACTICE AS A RESULT OF THIS EDUCATIONAL ACTIVITY?
    YES      NO       Please explain:


5. PLEASE RATE THE EASE OF PARTICIPATION IN THIS TELECONFERENCE:
    (difficult): 1 2 3 4 5 (easy)
                       Please explain:

6. WHAT OTHER CME ACTIVITIES WOULD HELP YOU OFFER MORE EFFECTIVE OR
   COST-EFFICIENT CARE FOR YOUR PATIENTS?




                                                                              Thank you for participating in this continuing medical education activity.
                                                                              Evaluations will be reviewed carefully and the results shared with the
                                                                              faculty. The information will be used to improve future CME activities.
NOTES
NOTES

				
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