1. The genetics of cystic fibrosis

2. Presentation Outline Cystic Fibrosis (CF) Screens/diagnostics
Get the article on ERES: McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet May 17;361(9370):
Cystic Fibrosis (CF)
Screens/diagnostics
Disease heritability
Gene & mutations
Genotype-phenotype
Outlook & discussion

3. Cystic Fibrosis
"Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die.“
-Northern European Folklore

4. Notable History 1838 Carl von Rokitansky’s autopsy of infant with
Meconium peritonitis
1905
Austrian Karl Landsteiner
describes Meconium ileus
1938
Cystic fibrosis disease
identified by American
Dorothy H. Andersen

5. Hallmarks of CF Very salty-tasting skin
Appetite, but poor growth & weight gain
Coughing, wheezing & shortness of breath
Lung infections, e.g. pneumonia/bronchitis

6. Clinical Aspects Cystic fibrosis affects the entire body
Lungs and sinuses
GI, liver and pancreas
Endocrine system
Reproductive system

7. The Sweat Test
Measures the concentration of chloride and sodium that is excreted in sweat.
Two reliable positive results on two separate days is diagnostic for CF.
Clinical presentation, family history and patient age must be considered to interpret the results.

8. Epidemiology CF is a rare disease CF is a disease of Caucasians.
Approximately 30,000 in the U.S. people have CF
Over 10 million Americans are unknowing carriers.
Around 2,500 children with CF are born each year.
CF is a disease of Caucasians.
Group
Incidence
Carriers
Delta F508
Caucasians
1 / 3,300
1 / 29
70%
Hispanics
1 / 9,000
1 / 46
46%
African Americans
1 / 15,300
1 / 60
48%
Asian Americans
1 / 32,100
1 / 90
30%

9. Heritability CF is a hereditary disease.
Unaffected parents can have children with CF.
Males and females are equally likely to be diagnosed.

10. Mapping the gene for CF
Gene linkage studies were able to map the mutation to chromosome 7.
Classical genetics techniques were not able to accurately pinpoint the mutated gene.

11. Mapping the gene for CF
1989: Lap-Chee Tsui, at the Hospital for Sick Children in Toronto, clones the CFTR gene. Victory tastes sweet.
Chromosome walking and jumping techniques were used
to identify and sequence the 180,000 bp gene.

12. The ΔF508 Mutation A 3 base pair deletion called ΔF508 is the most
common mutation causing cystic fibrosis
The mutation results in the deletion of a single
amino acid (Phe) at position 508.

13. Benefits of ΔF508 The ΔF508 mutation most likely occurred
over 50,000 years ago in Northern Europe.
Individuals with two copies of ΔF508 get cystic fibrosis and often cannot reproduce.
Having one copy of ΔF508 reduces water loss during cholera, greatly increasing the chance of survival.

14. The Function of CFTR CFTR encodes a 170 kDa, membrane-based
protein with an active transport function

15. From Mutation to Disease
The mutant form of CFTR
prevents chloride transport,
causing mucus build-up
Mucus clogs the airways
and disrupts the function of
the pancreas & intestines.

16. CFTR Mutations Over 1,000 mutations in CFTR have been found.
ΔF508 accounts for just
70% of CF cases.

17. 5 Classes of CFTR Mutations
CF Mutations can be classified by the effect they
have on the CFTR protein.

18. 5 Classes of CFTR Mutations
Defective
Production II
Defective
Processing
III
Defective
Regulation IV
Defective
Conductance V
Reduced
Amounts

19. Genotype Class and Mortality
Mutation class can affect disease mortality.

20. Genotype and Phenotype
Clinical phenotypes can vary widely across mutations

21. Newborn Screening Infants can easily be diagnosed with a blood test
Elevated levels of trypsinogen indicate CF
Screening programs identify 10% of cases at birth
Most hospitals do not screen for CF at birth.
Should they?

22. Genetic Carrier Testing
Tests for common CF mutations are available.
The type of defective CF gene can affect the type of CF symptoms.
However, genetic testing cannot fully determine how severe a person's CF will be in advance.

23. Further Reading The Cystic Fibrosis Foundation http://www.cff.org
McKone et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003.
The Cystic Fibrosis Mutation Database
The Cystic Fibrosis Foundation
Cystic Fibrosis on Wikipedia

24. Image Credits
and /wiki/CFTR_%28gene%29