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Genetic Testing for Cystic Fibrosis Dee Quinn, MS, CGC August, 2006.

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Presentation on theme: "Genetic Testing for Cystic Fibrosis Dee Quinn, MS, CGC August, 2006."— Presentation transcript:

1 Genetic Testing for Cystic Fibrosis Dee Quinn, MS, CGC August, 2006

2 “Gene Testing Going Mainstream” Cystic Fibrosis Gene Test Offered By Lauran Neergaard By Lauran Neergaard AP Medical Writer AP Medical Writer Monday, Oct. 1, 2001; 9:53 p.m. EDT Monday, Oct. 1, 2001; 9:53 p.m. EDT WASHINGTON –– Gene testing is going mainstream: Starting this month, tens of thousands of white Americans will be offered testing to see if they carry a gene mutation that causes cystic fibrosis even if no one in their family has the disease. WASHINGTON –– Gene testing is going mainstream: Starting this month, tens of thousands of white Americans will be offered testing to see if they carry a gene mutation that causes cystic fibrosis even if no one in their family has the disease.

3 CFTR Gene  Identified in 1989  Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)  27 exons, 250kB of genomic DNA  Chromosome 7q



6 CFTR Gene  cAMP-dependent chloride channel  Expressed in epithelial cells of:  respiratory tract  sweat and salivary glands  pancreas  intestine  reproductive tract

7 Clinical Phenotype  Respiratory  GI, pancreas  Reproductive

8 CFTR Mutations  Over 1,000 mutations identified  Most labs test for 25-87 mutations  13 of the identified CF mutations occur in more than 1% of CF chromosomes  72% of whites with CF are homozygous or heterozygous for 8 mutations  5 classes of CFTR mutations  Genotype/phenotype correlations may not be helpful


10 CFTR Mutations- ΔF508  Most common mutation in North America, 70-75% of the mutations  Deletion of codon 508  Results in shortening of the protein product  Protein product still functioning as Cl channel, but is retained in the endoplasmic reticulum  Δ F508 (homozygosity): classical phenotype

11 Epidemiology  One of the most common autosomal recessive diseases in Caucasians  Occurs in 1 in 3300 births  30,000 affected persons in the United States


13 Recessive Pedigree

14 Epidemiology 971/291/3,300Ashkenazi Jews 301/901/32,100Asian Americans 691/60-651/15,300African Americans 80-901/521/3,970-1/1,500Native Americans 571/461/8-9,000Hispanics 80-901/291/3,300Caucasians (United States) SensitivityCarrier Frequency IncidenceGroup

15 Congenital Bilateral Absence of the Vas Deferens (CBAVD)  Vas deferens – carries sperm from the epididymis to the ejaculatory ducts  Absence of vas occurs in 95% of males with CF  CBAVD: distinct genetic disorder which overlaps with CF and causes infertility  Noncoding region of CFTR gene involved: intron 8 with thymidine tracts (5T/7T/9T)  60-70% of men with CBAVD carry one mutation in the CFTR gene.  5T reduces the number of functional Cl channels

16 Congenital Bilateral Absence of the Vas Deferens (CBAVD)

17 Genotype - Phenotype Correlation CFTR Genotype CFTR Genotype First AlleleSecond Allele Range of Phenotypes Classic (e.g., F508)ClassicClassic >> nonclassic Mild (e.g., A455E)Classic or mildNonclassic > classic R117H/5TClassic or mildNonclassic > classic R117H/7TClassic or mildAsymptomatic female or CBAVD > nonclassic 5T/TG13 or TG12Classic or mildCBAVD or nonclassic CF >> asymptomatic carrier 5T/TG11Classic or mildAsymptomatic > CBAVD 7T or 9TClassic or mildAsymptomatic 7T or 9T7T or 9TAsymptomatic (From

18 Newborn Screening  Blood spots from infants taken within days of birth to identify infants at increased risk for a specific genetic disorders  Justifications: –Early treatment of respiratory illnesses –Evidence for nutritional benefit  Currently offered or in planning in many states – AZ to begin newborn screening by 9/07

19 Newborn Screening  Initial screen tests levels of IRT (immunoreactive trypsinogen)  Screening program should include: –Specific provider and patient educational materials –Protocol for addressing positive screening results  Sweat chloride  DNA testing –Development of systems in collaboration with specialty care providers to track short-term and long-term child outcomes and identify resources to support this activity

20 Carrier Screening for CF  1997- NIH convened a Consensus Conference  1998- ACOG/ACMG formed Steering Committee  10/2001- “Preconception and Prenatal Carrier Screening for Cystic Fibrosis”

21 ACOG/ACMG Recommendations  Offer screening to: –Individuals with a family history of CF –Reproductive partners of individuals with CF –Couples in whom one or both are Caucasian and are planning a pregnancy or seeking prenatal care –Other individuals must be given written information

22 ACOG/ACMG Recommendations  Provider’s Role : –Purpose of screening –Voluntary nature of screening –Symptoms of CF, treatment and prognosis –Genetics of CF and population frequencies –Meaning of positive and negative test results –Factors to consider in deciding to have or not to have screening

23 Additional Indications for Screening  Echogenic bowel detected on prenatal ultrasound  Infertility in males

24 Diagnostic Prenatal Tests  Testing offered when: –When both members of a couple are carriers, ie: 25% risk of having a baby with CF – When one member of a couple is carrier and other member not available for testing –Testing options:  Chorionic villus sampling (CVS) –9-11 weeks  Amniocentesis –After 14 weeks

25 Other Approaches  Procedure –In vitro fertilization –One cell removed from early embryo to test for mutations which were found in parents –Cell without a CF genotype transferred to mother’s uterus  Caveats –Technically demanding and complex procedure –Available on a limited basis –Expensive: $4,000 - $12,000 –Ethical implications

26 ACOG/ACMG Recommendations  Laboratory’s Role: Reports should include results of screening and an interpretation:  Negative  Residual risk given  Positive  Test other partner

27 Limitations of CF Screening  Does not detect all carriers  Estimate of residual risk applies only when family history is negative and to the current pregnancy  Cannot make reliable predictions for outcome based on mutations  Non-paternity

28 Genetic Counseling  Various outcomes of prenatal and newborn will generate need for genetic counseling: –Newly diagnosed child with CF –Healthy males who carry mutations associated with infertility –Identification of positive/negative couples who request additional mutational analyses or counseling to clarify residual risk –Positive/positive couples

29 Ethical, Legal, and Social Implications of CF Screening  Ethical  Unnecessary anxiety created  Inadequate pretest information  Legal  Informed Consent  Insurance discrimination  Social  Expense swell health costs  Societal pressure not to bear affected offspring

30 Resources  Cystic Fibrosis Foundation  GeneTests and GeneReviews  National Society of Genetic Counselors  Mountain States Genetics Network

31 Conclusions “It will be very important to see how this goes. Certainly it requires the obstetricians to become more familiar with genetics than many of them have previously had occasion to do.” -Francis Collins

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