Cystic fibrosis is an autosomal recessive genetic disorder; persons with cystic fibrosis have mutations in the gene encoding for the cystic fibrosis trans-membrane conductance regulator (CFTR) protein on both alleles of chromosome 7. Although >1,000 mutations on the CFTR gene have been identified, a single common mutation, ∆F508, accounts for two thirds of all cystic fibrosis alleles worldwide. This mutation is particularly frequent in persons of northern European ancestry, who also have the highest rates of cystic fibrosis, and is less common among persons of other ancestries. Because different populations have different mutation frequencies, the sensitivity of a given DNA mutation panel for detecting persons with cystic fibrosis varies by race and ethnicity,and including mutations specific to racial and ethnic minority populations can improve detection of cystic fibrosis among those populations.
Because of differing frequencies of CFTR mutations, the birth prevalence of cystic fibrosis varies by race/ethnicity. On the basis of data from U.S. newborn screening programs, birth prevalence is 1/2,500-3,500 births among non-Hispanic whites,1/4,000-10,000 births among Hispanics, and 1/15,000-20,000 births among non-Hispanic blacks. Non-Hispanic whites, who in 2000 accounted for 56% of births in the United States, constituted >90% of U.S. patients who received a diagnosis of cystic fibrosis. On the basis of data from state newborn screening programs that included cystic fibrosis in 2000, the overall birth prevalence of cystic fibrosis in the United States is approximately 1/3,700. It is more common than PKU (1/20,000) and galactosemia (1/67,000) and less common than congenital hypothyroidism (1/2,500) and SCD (1/2,600).
Mutations in the CFTR gene can alter the structure, function, or production of a cyclic adenosine-5'-monophosphate (AMP)-dependent trans-membrane chloride channel protein that is critical for normal functioning of multiple organs. The organs and systems that are affected in cystic fibrosis include the lungs and upper respiratory tract, gastrointestinal tract, pancreas,liver, sweat glands, and genitourinary tract. For example, defective salt re-absorption in sweat glands leads to overly salty sweat and, in certain cases, to electrolyte imbalance, dehydration, and death.
Deficient chloride transport in the lungs is thought to result in the production of abnormally thick mucus, which in turn is believed to lead to airway obstruction, neutrophil-dominated inflammation, and recurrent and progressive pulmonary infections. The combination of inflammation and infection accounts for the pulmonary symptoms related to cystic fibrosis. Acute viral respiratory infections, common to all children, are much more likely to develop into lower respiratory tract infections among children with cystic fibrosis, resulting in hospitalization and acquisition of chronic bacterial infections.
Pancreatic insufficiency, which results from virtually absent pancreatic enzyme activity, is present at diagnosis among>80% of persons with cystic fibrosis and increases with age to >90%. Pancreatic insufficiency causes fat and protein malabsorption. Gastrointestinal symptoms associated with fat mal-absorption include loose, foul-smelling fatty stools (steatorrhea) and abdominal pain. Nutritional consequences of pancreatic insufficiency include fat-soluble vitamin deficiencies and growth failure. Persons with cystic fibrosis who have normal or subnormal pancreatic enzyme activity, referred to as pancreatic sufficiency, rarely experience nutrition-related symptoms but are at risk for pancreatitis as they age. They also experience fewer pulmonary problems and have lower mortality.
Research into genotype-phenotype associations in cystic fibrosis indicates that both pancreatic insufficiency and pancreatic sufficiency are associated with specific CFTR mutations. CFTR gene mutations have been placed into five classes. The first three are associated with complete loss of cyclic AMP-regulated chloride channel function and are identified as "severe" mutations. Mutations in the other two might allow for residual CFTR function and therefore are usually associated with milder phenotypes and pancreatic sufficiency. Persons who have two mutations from within classes I, II, or III almost invariably experience pancreatic insufficiency, and those with <2 mutations from classes IV or V usually maintain pancreatic insufficiency. The common ∆F508 mutation is a class II mutation that is associated with pancreatic insufficiency. Not all CFTR mutations have been identified or classified.
Example of an Inheritance Pattern for Cystic Fibrosis
The image shows how CFTR genes are inherited. A person inherits two copies of the CFTR gene - one from each parent. If each parent has a normal CFTR gene and a faulty CFTR gene, each child has a 25 percent chance of inheriting two normal genes; a 50 percent chance of inheriting one normal gene and one faulty gene; and a 25 percent chance of inheriting two faulty genes.