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Genetic Testing for Cystic Fibrosis. Dee Quinn, MS, CGC August, 2009. “Gene Testing Going Mainstream”. Cystic Fibrosis Gene Test Offered By Lauran Neergaard AP Medical Writer Monday, Oct. 1, 2001; 9:53 p.m. EDT

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Genetic Testing for Cystic Fibrosis

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Genetic testing for cystic fibrosis

Genetic Testing for Cystic Fibrosis

Dee Quinn, MS, CGC

August, 2009

Gene testing going mainstream

“Gene Testing Going Mainstream”

Cystic Fibrosis Gene Test Offered

By Lauran Neergaard

AP Medical Writer

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.



  • One of the most common autosomal recessive diseases in Caucasians

  • Occurs in 1 in 3300 births

  • 30,000 affected persons in the United States






Sensitivity of Mutation Analysis


(United States)




Ashkenazi Jews








Native Americans




African Americans










Worldwide distributions of cystic fibrosis gene mutations

Worldwide Distributions of Cystic Fibrosis Gene Mutations

O'Sullivan, B, Freedman, S. Cystic Fibrosis. Lancet 2009; 373:1891-1904

Autosomal recessive inheritance

Autosomal Recessive Inheritance

Family history

Family History

Cftr gene


  • CFTR - cystic fibrosis transmembrane conductance regulator

  • Chromosome 7q31.2

  • Identified in 1989

  • Composed of 27 exons, 250kB of genomic DNA

  • Gene product is a 1480-amino acid membrane protein that functions as a regulated chloride channel in epithelial cells

  • More than 1500 mutations have been found in this gene

Cftr gene1


  • Expressed in epithelial cells of:

    • respiratory tract

    • sweat and salivary glands

    • pancreas

    • intestine

    • reproductive tract

  • Responsible for:

    • CF

    • CBAVD

    • Chronic sinusitis

Clinical phenotype

Clinical Phenotype

Ratjen, F. Cystic fibrosis: Pathogenesis and future treatment strategies. Respir Care 2009; 54(5): 595-602.

Clinical phenotype1

Clinical Phenotype

  • Respiratory

  • GI, pancreas

  • Reproductive

  • Current life expectancy 31-37 years

  • UK study estimated life expectancy

    for child born today with CF is 50

Cftr mutation testing

CFTR Mutation Testing

  • Most labs test for 25-97 mutations

  • 10 of the identified CF mutations occur in more than 1% of CF chromosomes

  • Most common mutation (Δ F508) found in 66% of individuals with CF

  • 5 classes of CFTR mutations

  • Genotype/phenotype correlations may be helpful in predicting pancreatic sufficiency

Effects of gene mutations

Effects of Gene Mutations

  • Class I, II and III mutations are more common and associated with pancreatic insufficiency

  • Class IV and V are less common and usually associated with pancreatic sufficiency

  • CFTR gene interacts with other intracellular proteins which may affect clinical symptoms

Cftr mutations f508

CFTR Mutations- ΔF508

  • Most common mutation in North America

  • Deletion of phenylalanine in codon 508  misfolded protein

  • Protein product still functioning as Cl channel, but is degraded in the endoplasmic reticulum

  • ΔF508 (homozygosity): classical phenotype

Effects of common mutations

Effects of Common Mutations

Moskowitz, SM, Clinical practice and genetic counseling for cystic fobrosis and CFTR_related disorders. Genet Med 2008; 10(12): 851-868

Gene based therapies

Gene-based Therapies

  • Gene therapy

    • uses viral vector

    • Still being developed

  • Ataluren trial

    • Drug which “reads through” stop codons

    • Currently beginning phase 3 trials

    • Can only be used for individuals who have CF mutation as result of nonsense mutations (Class I)

    • Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein.

Clinical phenotype congenital bilateral absence of the vas deferens cbavd

Clinical Phenotype - 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

Congenital bilateral absence of the vas deferens cbavd

Congenital Bilateral Absence of the Vas Deferens (CBAVD)

Newborn screening

Newborn Screening

  • Screening program should include:

    • Specific provider and patient educational materials

    • Protocol for addressing positive screening results

    • 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

  • Blood spots from infants taken within days of birth to identify infants at increased risk for a specific genetic disorders

Newborn screening for cystic fibrosis

Newborn Screening for Cystic Fibrosis

  • Tests for immunoreactivetrypsinogen (IRT), repeat IRT if elevated

  • Trypsinogen is synthesized in the pancreas

  • Individuals with CF have elevated levels of trypsinogen, regardless of pancreatic sufficiency

  • Currently offered in most states – AZ began

    newborn screening in 11/07

  • Important for:

    • Early treatment of respiratory illnesses

    • Evidence for nutritional benefit

  • Diagnostic test is sweat chloride test

  • DNA testing is important for family planning and new treatments

Acog acmg recommendations for prenatal screening

ACOG/ACMG Recommendations For Prenatal Screening

  • 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

  • Additional indications for screening

    • Echogenic bowel detected on prenatal ultrasound (15% of infants with CF have meconiumileus)

    • Infertility in males

Acog acmg recommendations

ACOG/ACMG Recommendations

  • Provider’s Role:

    • Purpose of screening

    • Voluntary nature of screening

    • Symptoms of CF, treatment and


    • Genetics of CF and population


    • Meaning of positive and negative test


    • Factors to consider in deciding to have

      or not to have screening

Diagnostic prenatal tests

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

Other approaches

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

Limitations of cf screening

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

Genetic counseling

Genetic Counseling

  • Various outcomes of prenatal and newborn testing 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

Ethical legal and social implications of cf screening

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



  • Cystic Fibrosis Foundation

  • GeneTests and GeneReviews

  • National Society of Genetic Counselors

  • Mountain States Genetics Network



“It will be very important to see how this goes. Certainly it requires primary care providers to become more familiar with genetics than many of them have previously had occasion to do.”

-Francis Collins

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