Dedicated to those seeking a better understanding of the Cystic Fibrosis mutation and the risk of passing on the defect.

Case Study #1

Barbara McClintlock and George M. Church requested genetic counseling and DNA sampling to predict genetic disease risks associated with having children.  

The findings of their DNA testing is presented in the following Punnett squares with summaries of the genotypes and phenotypes, and a written summary of the findings.

Case Study #1 data

Insert punnet squares

Case Study #1 - Achondroplasia

Case Study #1 - Cystic Fibrosis

Case Study #1 - Huntington's Disease

Case Study #1 Summary

In Case Study #1, the offspring will have no chance of inheriting the dominant gene needed for either Achondroplasia or Huntington’s Disease because both parents have only recessive genes.  Autosomal dominant traits do not have unaffected carriers, so the offspring will not be carriers of either Achondroplasia or Huntington’s Disease.

However, the offspring will have a 50% chance to inherit Cystic Fibrosis and a 50% chance to be a carrier of CF because the mother is a carrier of the mutation and the father has only recessive genes and must have CF.  Because CF is an autosomal recessive trait, the offspring must inherit a copy of the affected recessive gene from both parents to have CF.  If a child inherits an affected recessive gene from only one parent, the child will carry CF but will not be affected by it.  

In this case, the offspring will be either an unaffected carrier of one recessive mutated gene or have CF (with copies of both recessive mutated genes).

Cystic Fibrosis disrupts the normal secretion functions of epithelial cells. 

Epithelial cells form sweat glands in the skin and also line passageways inside the lungs, liver, pancreas, and digestive and reproductive systems.

What is Cystic Fibrosis? 

    - disruption of secretion functions of epithelial cells

Disruption of normal functions

Cystic Fibrosis is a genetic defect in the CFTR gene which makes the CFTR protein. 

CFRT stands for “cystic fibrosis transmembrane conductance regulator.” 

The CFTR protein is an important chloride channel that pumps ions in and out of the cell. 

When epithelial cells contain defective CFTR protein channels, epithelial cells are unable to regulate the way that chloride passes across cell membranes and that interferes with the normal channeling of water in tissues. 

What is Cystic Fibrosis?  

    - genetic defect in the CFTR gene that makes CFTR protein

What is Cystic Fibrosis?  

    - thick and sticky mucus causes problems

This dysfunctional CFTR protein channel causes the cells’ secretions, mucus, to be sticky and thick instead of acting normally as a lubricant for the body. 

This thick and sticky mucus causes blockages in the body’s tubes, ducts, and passages that interfere with the body’s normal functions, mainly in the respiratory and digestive systems. 

What is Cystic Fibrosis?  

        - a progressive and fatal disease 

Cystic Fibrosis is a progressive and fatal disease that over time and eventually accumulates so much damage to the lungs that the lungs fail to deliver oxygen.

What is Cystic Fibrosis?  

        - a progressive and fatal disease that runs in families

Because Cystic Fibrosis is a genetic disease, it runs in families.

The Discovery of Cystic Fibrosis as a Disease 

    -symptoms recognized for centuries

The symptoms of Cystic Fibrosis have been recognized for centuries.

In 1595, Professor Pieter Pauw wrote the earliest medical description that was certainly cystic fibrosis, noting salty skin, pancreatic damage, and other observations in a child’s autopsy.

Even an ancient Germanic folk saying recognized that salty skin (found in CF children) foretold a short life: 

                    “Woe to that child which when kissed on the forehead tastes salty. 

                        He is bewitched and soon must die.”

The Discovery of Cystic Fibrosis as a Disease 

     -modern medical recognition of the disease

Nevertheless, medical recognition that all these symptoms were a singular disease began in the 20th century.

The Discovery of Cystic Fibrosis as a Disease 

     - "cystic fibrosis of the pancreas"

The first modern report of cystic fibrosis in a scientific paper was in a 1936 paper by Dr. Guido Fanconi entitled, “Celiac syndrome with congenital cystic fibromatosis of the pancreas and bronchiectasis.” 

In 1938, Dr. Dorothy Andersen, a pathologist, authored the first comprehensive account of the cyst formation and scarring of the pancreas or “cystic fibrosis of the pancreas” as a distinct disease.  Her findings regarding the disease were based on autopsies of children who died from malnutrition.  

Dr. Dorothy Anderson

Dr. Guido Faconi

The Discovery of Cystic Fibrosis as a Disease 

     - sweat electrolyte defect

In 1948, Dr. Paul di Sant’Agnese linked children with abnormally salty sweat to the condition, which led to the 1953 discovery of the sweat electrolyte defect and the beginning of the use of the sweat test.  

In the 1950s, the Cystic Fibrosis Foundation was organized and began funding cystic fibrosis research by Dr. Andersen, Dr. di Sant'Agnese, and others. 

Dr. Paul di Sant'Agnese

The Discovery of Cystic Fibrosis as a Disease 

         - CFTR protein

However, it was not until the 1980s that the defective CFTR protein was identified, and once DNA sequencing was available, the genetic defect responsible for CF was discovered in 1989.

How many people have Cystic Fibrosis?  

Cystic Fibrosis affects about 30,000 children and adults in the United States and about 70,000 people worldwide.   

It is far more common in Northern European Caucasian populations and is the most common autosomal recessive genetic disorder among Caucasians. 

Although CF is more commonly found in the white population, the disease affects all racial and ethnic groups. 

What is the birth rate frequency?

Cystic Fibrosis occurs in approximately one in 3,000 – 4,000 Caucasians live births. 

Approximately one in 25–30 Caucasians are carriers of a mutation of the CFTR gene.  

In other races and ethnicities, CF occurs less frequently, including approximately:

 One in 4,000 – 10,000 Latin Americans, 

 One in 15,000 – 20,000 African Americans, 

 and even less commonly in Asian Americans.

Geographic distribution of Cystic Fibrosis

The incidence rates vary worldwide, and the geographic distribution is shown below.

Origins of Cystic Fibrosis

The origin of Cystic Fibrosis has been traced to a Bronze Age European group who lived about 5,000 years ago.  

A population known as the Bell Beaker folk have been identified as the likely migrating population responsible for spreading the CF mutation in regions that correspond closely to the present-day European Union, where the highest incidence of CF is found.

A bell beaker made by the Bell Beaker folk

Origins of Cystic Fibrosis

The CF mutation arose in the early Bronze Age and spread from west to southeast Europe during ancient migrations of the Bell Beaker group over the course of 1000 years.

Distribution of Bell Beaker sites throughout Europe.pe.

Does Cystic Fibrosis affect males and females equally?

Cystic fibrosis occurs equally as often in men and women. 

Being an autosomal genetic disorder, the genetic mutation for cystic fibrosis occurs on Chromosome 7 and is not impacted by gender. 

However, women overall have more severe disease symptoms than men with CF and a shorter life expectancy. 

Causes:  Is the disease autosomal dominant or autosomal recessive?

Cystic Fibrosis is an autosomal recessive genetic defect, meaning that the offspring must inherit a mutated recessive gene from both parents to have CF.   But unaffected carriers of the disease only need to inherit a mutated recessive gene from one parent.

What chromosome is affected?

The CFTR (cystic fibrosis transmembrane regulator) gene is located on Chromosome 7.  Mutations in this gene are what cause CF. 

The CFTR  gene is very large and complex.  More than 1,800 different mutations in this gene have been found that cause CF.

Chromosome 7 of 23 

CFTR Gene Scheme - large & complex

How is the chromosome affected? 

(Is it a deletion, insertion, substitution, etc.?)

In the most common Cystic Fibrosis mutation (66%), Chromosome 7 is affected by a deletion of a phenyl-alanine in position 508 on the CFTR gene.

The 508 Deletion

About 90 percent of Cystic Fibrosis patients in the U.S. and Europe have at least one 508 deletion mutation.

This tiny mutation causes loss of one amino acid out of the  1,480 amino acid chain in the CFRT protein.  This changes the shape of the CFRT protein so that it cannot move chloride in and out of the cell.                8    

Symptoms: 

    -overview

People with Cystic Fibrosis have (1) elevated sweat electrolyte levels, (2) pancreatic and liver insufficiency, 

(3) respiratory infections,   

(4) gastro-intestinal problems, and (5) fertility problems.

Symptoms: 

    -overview

Cystic Fibrosis mainly affects the lungs, the pancreas, the liver, the intestines and the sinuses. 

Most people with CF have these problems, but because the disease severity varies among individuals, not all people have all of these symptoms or may have some symptoms but not all of the time.

Symptoms Vary

Symptoms: 

    -organs affected:  lungs & respiratory tract

The most prominent organ affected are the lungs due to excess mucus that traps bacteria and causes persistent lung infections and permanent damage.  

Because CF affects the epithelium lining of the sinuses and upper respiratory tract, people with CF often have inflammation and infection of the sinuses.

Symptoms: 

    -lungs & respiratory tract symptoms

The symptoms of these Cystic Fibrosis respiratory complications include: 

                                -a persistent cough, 

                                -wheezing, 

                                -stuffy nose, 

                                -repeated lung infections, 

                                -recurrent sinus infections, and

                                -exercise intolerance.

Exercise Intolerance

Sinus Infection

Symptoms: 

    -organs affected:  pancreas, liver, & intestines

The pancreas, liver, and intestines are also unable to function normally with Cystic Fibrosis.  

CF interferes with normal digestion of fats and proteins because excess mucus blocks digestive enzymes from the liver and pancreas from reaching the intestines.  

Symptoms: 

    -pancreatic, liver, & intestinal symptoms

This lack of liver and pancreatic digestive enzymes in the intestines can lead to severe malnutrition because the body is unable to digest or absorb fat and protein nutrients. 

The symptoms of CF intestinal malfunction include: 

-foul-smelling, greasy stools, 

-poor weight-gain and growth from malnutrition, 

-intestinal pain from blockages and from chronic or severe constipation, and 

-lack of energy.

Poor weight gain

Intestinal pain

Lack of Energy

Symptoms: 

    -pancreatic symptoms

Because of the build up of enzymes in the pancreas, Cystic Fibrosis can cause the pancreas to become inflamed and scarred.  The pancreas then functions less effectively, which then leads to  Cystic Fibrosis related diabetes (CFRD).

Symptoms: 

    - liver symptoms

 Cystic Fibrosis can cause liver disease due to inflamed or blocked bile ducts. About 10-20% of people with CF develop liver disease, which includes cirrhosis, a buildup of fat in the liver, hepatitis, and other complications. 

Liver Affected by CF