Cystic Fibrosis Screening

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Cystic Fibrosis Screening

• Robert Resta, M.S., C.G.C
• Director of Genetic Counseling Services
• Division of Perinatal Medicine
• Swedish Medical Center
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ACOG/ACMG Guidelines For CF Screening

• Individuals with a family hx of CF
• Reproductive partners of CF patients
• Caucasian couples who are pregnant or planning a
  pregnancy
• Make screening available to other ethnic
  groups if pregnant/planning pregnancy

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CF Symptoms

• Chronic sino-pulmonary disease
• Gastrointestinal/nutritional problems
• Salt-loss syndromes
• Normal intellect
• Life span about 30 years
• If pancreatic sufficient, life span 56 years

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CF Symptoms

• Severity is extremely variable
• Males have obstructive azoospermia
• Females have reduced fertility
• Pregnant females at ? risk FOR OB complications,
  especially if pulmonary insufficient

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CF Treatment

• Antibiotics
• Mucolytics
• Chest physiotherapy
• Enzyme/vitamin supplementation
• Heart/Lung transplant
• Gene therapy still experimental

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CF Genetics

• Autosomal recessive, i.e., both parents must be
  carriers
• If carriers, 1/4 (25) risk of affected child,
  with each pregnancy, regardless of sex of child
• Carriers usually asymptomatic
• Usually no family history of CF

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CF Genetics

• Most common genetic disease in N/W Europeans
• Carrier Frequency in N/W Europeans 1/28
• Disease Incidence in N/W Europeans 1/3300
  births
• Carrier and disease frequency much lower in
  other populations

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CF Genetics
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CF Genetics

• CF gene identified in 1989
• Maps to long arm of chromosome 7
• Gene called CFTR (cystic fibrosis transmembrane
  conductance regulator)
• Membrane protein, epithelial chloride channel

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Location of CF Gene on Chromosome 7
Reprinted with permission from Schuler et al.,
Science 274, 540 (1996). American Association for
the Advancement of Science
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CFTR Is A Membrane Protein
IMAGE CREDIT Q. Alawqati, Columbia University,
NY, USA. Adapted by K. Sutliff, SCIENCE
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CF Genetics

• More than 900 mutations in the CFTR gene
• Mutations result in reduced synthesis, blocked
  protein processing, blocked regulation of
  chloride channel, or altered conductance of
  chloride channel

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Common Mutations(adapted from ACOG, 2001)
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CF Genetics

• Mutations in other populations not well
  characterized
• Mutations do not always predict severity of
  disease

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CF Carrier Screening

• DNA test
• Not affected by pregnancy
• Works equally well in both sexes
• Should be done prior to, or very early in,
  pregnancy

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CF Carrier Screening

• 5-10 ccs whole blood
• Purple or yellow top tube
• No special handling required
• Room temperature okay
• Very important to identify ethnicity to lab

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CF Carrier Screening

• Test available through most major labs
• Cost 225-350 per patient
• Test patient OR partner
• If one negative, no need to test other

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CF Carrier Screening

• ACOG/ACMG recommend screening for 25 most common
  mutations
• This should detect 90 of N/W European carriers
  and 95 of Ashkenazi carriers
• Carrier detection rate in other populations much
  lower

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CF Carrier Screening
Adapted from ACOG (2001)
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CF Carrier Screening

• A normal result means a lower chance of being a
  carrier and of having an affected child.
• Screening does not detect all carriers!!

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CF Carrier Screening
Adapted from ACOG (2002)
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CF Carrier Screening

• False positives are rare
• Fetus at risk if the patient and partner carry
  different mutations (
  i.e., compound heterozygote)

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CF Management of Results

• If patient negative, go no further
• If positive, refer for genetic counseling
• If positive, test partner
• If partner negative, go no further

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CF Management of Results

• If patient and partner positive, 1/4 chance of
  affected child
• Amniocentesis or CVS
• If patient OR partner positive, other relatives
  should be notified

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CF Male Infertility

• 80 of males with CBAVD are CF carriers or
  homozygotes
• 5T allele normally benign unless occurs with
  other CF mutation
• 30 of males with CUAVD are CF carriers
• Refer these men for genetic counseling

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CF High Risk Patients

• Males with bilateral/unilateral absence of vas
  deferens
• Patient or partner with family history of CF
• Fetus with echogenic bowel
• Refer all of above for genetic counseling

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References

• American College of Obstetricians and
  Gynecologists, American College of Medical
  Genetics (2001) Preconception and prenatal
  carrier screening for cystic fibrosis. ACOG
  Washington, DC.
• Chillon M et al (1995) Mutations in the cystic
  fibrosis gene in patients with congenital absence
  of the vas deferens. NEJM 3321475-1480.
• Doull IJ (2001) Recent advances in cystic
  fibrosis. Arch Dis Child 85(1)62-66.
• Edenborough FP (2001) Women with cystic fibrosis
  and their potential for reproduction. Thorax
  56(8)649-655.
• Flotte R, Laube BL (2001) Gene therapy in cystic
  fibrosis. Chest 120(3)124S-131S.

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References (2)

• Le Maréchal C, Audrézet MP, Quéré I, Raguénès O,
  Langonné S, Férec C (2001) Complete and rapid
  scanning of the cystic fibrosis transmembrane
  conductance regulator (CFTR) gene by denaturing
  high-performance liquid chromatography (D-HLPC)
  major implications for genetic counselling. Hum
  Genet 108290-298.
• Noone, PG, Knowles MR (2001) CFTR-opathies
  disease phenotypes associated with cystic
  fibrosis transmembrane regulator gene mutations.
  Respir Res 2328-332.
• Orenstein DM, Winnie GB, Altman H (2002) Cystic
  fibrosis A 2002 Update. J Pediatr 140156-164.
• Robinson P (2001) Cystic fibrosis. Thorax 56(3)
  237-241.

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Helpful Web Sites

• GeneReviews http//www.geneclinics.org
• CF Mutation Site - http//www.genet.sickkids.on.ca
  /
• General Information for Public and Physicians -
  http//www.cysticfibrosis.co.uk
• Cystic Fibrosis Foundation - http//www.cff.org/

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