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The genetics of cystic fibrosisThe genetics of cystic fibrosis

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Presentation OutlinePresentation Outline

I.I. Cystic Fibrosis (CF)Cystic Fibrosis (CF)II.II. Screens/diagnosticsScreens/diagnosticsIII.III. Disease heritabilityDisease heritabilityIV.IV. Gene & mutationsGene & mutationsV.V. Genotype-phenotypeGenotype-phenotypeVI.VI. Outlook & discussionOutlook & discussion

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. 2003 May 17;361(9370):1671-6.

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Cystic FibrosisCystic 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

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Notable HistoryNotable History

19051905Austrian Karl Landsteiner Austrian Karl Landsteiner describes Meconium ileusdescribes Meconium ileus

19381938Cystic fibrosis disease Cystic fibrosis disease identified by American identified by American Dorothy H. Andersen Dorothy H. Andersen

18381838Carl von Rokitansky’s Carl von Rokitansky’s autopsy of infant withautopsy of infant withMeconium peritonitisMeconium peritonitis

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Hallmarks of CF Hallmarks of CF

Very salty-tasting skin Very salty-tasting skin Appetite, but poor Appetite, but poor growth & weight gaingrowth & weight gainCoughing, wheezing Coughing, wheezing & shortness of breath & shortness of breath Lung infectionsLung infections, e.g. , e.g. pneumonia/bronchitis pneumonia/bronchitis

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Clinical AspectsClinical Aspects

Cystic fibrosis affects the entire bodyCystic fibrosis affects the entire body

• Lungs and sinusesLungs and sinuses

• GI, liver and GI, liver and pancreaspancreas

• Endocrine system Endocrine system

• Reproductive systemReproductive system

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The Sweat TestThe Sweat Test

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

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EpidemiologyEpidemiology

CF is a CF is a rarerare disease diseaseApproximately 30,000 in the U.S. people have CFApproximately 30,000 in the U.S. people have CFOver 10 million Americans are unknowing carriers.Over 10 million Americans are unknowing carriers.Around 2,500 children with CF are born each year.Around 2,500 children with CF are born each year.

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%

CF is a disease of CF is a disease of CaucasiansCaucasians..

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HeritabilityHeritability

CF is a CF is a hereditaryhereditary disease. disease.

Unaffected parents can have Unaffected parents can have children with CF.children with CF.

Males and females are equally Males and females are equally likely to be diagnosed.likely to be diagnosed.

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Mapping the gene for CFMapping the gene for CF

Gene linkage studies were able to Gene linkage studies were able to map the mutation to chromosome 7.map the mutation to chromosome 7.

Classical genetics techniques were Classical genetics techniques were not able to accurately pinpoint the not able to accurately pinpoint the mutated gene.mutated gene.

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Mapping the gene for CFMapping the gene for CF19891989: Lap-Chee Tsui, at the Hospital for Sick Children in : Lap-Chee Tsui, at the Hospital for Sick Children in

Toronto, clones the Toronto, clones the CFTRCFTR gene. Victory tastes sweet. gene. Victory tastes sweet.

Chromosome Chromosome walkingwalking and and jumpingjumping techniques were used techniques were used to identify and sequence the 180,000 bp gene.to identify and sequence the 180,000 bp gene.

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The ΔF508 MutationThe ΔF508 Mutation

The mutation results in the deletion of a single The mutation results in the deletion of a single amino acid (Phe) at position 508.amino acid (Phe) at position 508.

A 3 base pair deletion called A 3 base pair deletion called ΔF508ΔF508 is the most is the most common mutation causing cystic fibrosiscommon mutation causing cystic fibrosis

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Benefits of ΔF508Benefits of ΔF508

The ΔF508 mutation most likely occurred The ΔF508 mutation most likely occurred over 50,000 years ago in over 50,000 years ago in Northern EuropeNorthern Europe..

Individuals with two copies of ΔF508 get cystic Individuals with two copies of ΔF508 get cystic fibrosis and often cannot reproduce.fibrosis and often cannot reproduce.

Having one copy of ΔF508Having one copy of ΔF508 reduces water loss reduces water loss during during choleracholera, greatly increasing the chance of , greatly increasing the chance of survival.survival.

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The Function of CFTRThe Function of CFTR

CFTR encodes a 170 kDa, membrane-based CFTR encodes a 170 kDa, membrane-based protein with an active protein with an active transporttransport function function

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From Mutation to DiseaseFrom Mutation to DiseaseThe mutant form of CFTR The mutant form of CFTR prevents chloride transport, prevents chloride transport, causing mucus build-upcausing mucus build-up

Mucus clogs the airways Mucus clogs the airways and disrupts the function of and disrupts the function of the pancreas & intestines. the pancreas & intestines.

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CFTR MutationsCFTR Mutations

Over Over 1,0001,000 mutations in mutations in CFTR have been found.CFTR have been found.

ΔF508 accounts for just ΔF508 accounts for just 70%70% of CF cases. of CF cases.

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5 Classes of CFTR Mutations5 Classes of CFTR Mutations

CF Mutations can be classified by the CF Mutations can be classified by the effecteffect they they have on the CFTR protein.have on the CFTR protein.

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5 Classes of CFTR Mutations5 Classes of CFTR Mutations

IDefective

Production

IIDefective

Processing

IIIDefective

Regulation

IVDefective

Conductance

VReduced

Amounts

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Genotype Class and MortalityGenotype Class and Mortality

Mutation class can affect disease Mutation class can affect disease mortalitymortality..

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Genotype and PhenotypeGenotype and PhenotypeClinical phenotypesClinical phenotypes can vary widely across mutations can vary widely across mutations

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Newborn ScreeningNewborn Screening

Infants can easily be diagnosed with a blood testInfants can easily be diagnosed with a blood testElevated levels of trypsinogen indicate CFElevated levels of trypsinogen indicate CFScreening programs identify 10% of cases at birth Screening programs identify 10% of cases at birth

Most hospitals Most hospitals do not screendo not screen for CF at birth. for CF at birth.Should they?Should they?

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Genetic Carrier TestingGenetic Carrier Testing

Tests for common CF mutations Tests for common CF mutations are available.are available.

The type of defective CF gene The type of defective CF gene can affect the type of CF can affect the type of CF symptoms.symptoms.

However, genetic testing However, genetic testing cannotcannot fully determine how severe a fully determine how severe a person's CF will be in advance. person's CF will be in advance.

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Further ReadingFurther Reading

The Cystic Fibrosis FoundationThe Cystic Fibrosis Foundationhttp://www.cff.orghttp://www.cff.org

Cystic Fibrosis on WikipediaCystic Fibrosis on Wikipediahttp://en.wikipedia.org/wiki/Cystic_fibrosishttp://en.wikipedia.org/wiki/Cystic_fibrosis

McKone et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003.

The Cystic Fibrosis Mutation Databasehttp://www.genet.sickkids.on.ca/cftr

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