Cystic Fibrosis (CF) is an inherited condition that primarily affects the lungs and digestive system, causing the production of thick, sticky mucus. This disorder is classified as a multisystem disease because it impacts various organs, including the pancreas, liver, and intestines. Understanding the genotype is fundamental to comprehending how this condition develops. The specific combination of gene variants dictates whether a person has CF, is a carrier, or is unaffected.
The Genetic Foundation: The CFTR Gene
Cystic fibrosis is caused by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This gene is situated on the long arm of human Chromosome 7 at location q31.2 and provides the blueprint for creating the CFTR protein. This protein functions as a channel embedded in the membranes of cells that line various passageways, such as those in the lungs, pancreas, and sweat glands. The normal function of the CFTR protein is to regulate the movement of chloride ions and water across the cell membrane. This movement is necessary to maintain the thin, free-flowing consistency of mucus and other bodily secretions. Each person inherits two copies, or alleles, of the CFTR gene, one from each biological parent.
Defining the Cystic Fibrosis Genotype
A person develops cystic fibrosis only when they inherit two copies of the CFTR gene that contain a disease-causing alteration, known as a mutation. Since CF is an autosomal recessive condition, both alleles must be affected for the disease to manifest. The specific CF genotype is defined by the pair of mutations present on these two gene copies.
The most frequently occurring mutation worldwide is a deletion called Delta F508 (\(\Delta\)F508), which accounts for the majority of all CF cases. This single deletion results in the loss of one amino acid at position 508 in the CFTR protein structure. Individuals who inherit the same mutation on both copies of the gene, such as \(\Delta\)F508/\(\Delta\)F508, are described as homozygous for that mutation.
A person can also have a compound heterozygous genotype by inheriting two different CF-causing mutations, such as \(\Delta\)F508 on one allele and G551D on the other. Scientists have identified over 2,000 different mutations in the CFTR gene that can potentially cause the condition, illustrating the wide variety of possible CF genotypes.
How Genotype Dictates Disease Severity
The specific combination of mutations in the CFTR genotype directly influences the severity of the disease symptoms. Mutations are categorized into six classes based on how they affect the production and function of the CFTR protein.
Severe Genotypes (Classes I, II, and III)
These classes typically lead to the most severe forms of the disease. Class I results in no CFTR protein production. Class II (which includes \(\Delta\)F508) produces protein that is immediately degraded before reaching the cell surface. Class III mutations result in the protein reaching the surface but having a non-functional channel. Individuals with these genotypes commonly experience pancreatic insufficiency, requiring supplemental digestive enzymes.
Milder Genotypes (Classes IV, V, and VI)
These mutations are associated with a milder presentation of cystic fibrosis due to some residual protein function. Class IV mutations create a channel that conducts chloride ions poorly. Class V mutations cause a reduced amount of functional protein to be made. These genotypes may allow for some degree of pancreatic function, classifying the individual as pancreatic sufficient, and often lead to a later diagnosis and a less aggressive disease course.
Understanding Carrier Status and Inheritance
Cystic fibrosis follows an autosomal recessive inheritance pattern, requiring two mutated copies for the disease to occur. A person is considered a carrier if they possess one functional CFTR allele and one mutated CFTR allele. Carriers are heterozygous and typically do not exhibit any symptoms of cystic fibrosis because the single functional gene copy is sufficient to produce enough CFTR protein for normal bodily function.
If two carriers of a CFTR mutation have a child, the probability for inheritance with each pregnancy is:
- 25% chance the child will inherit a mutated allele from both parents and have cystic fibrosis.
- 50% chance the child will be a carrier, inheriting one mutated allele.
- 25% chance the child will inherit two functional copies and be completely unaffected.
This model explains how the disease can unexpectedly appear in families with no prior known history of the condition.