Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

Abstract

Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.

Cystic fibrosis carrier screening in a North American population

“…1 To date, more than 1,900 unique mutations have been described in the CFTR gene. 2 The observed phenotypic heterogeneity of CF is due to the variable impact of the underlying mutations, in combination with the action of genetic modifiers and environmental factors.…”

“…3 The phenotypic spectrum of CF ranges from a mild disease, found in ~15% of CF patients, to a progressive, multisystem disease primarily involving the pulmonary, pancreatic, and gastrointestinal systems. 1,4 Individuals with a mild form of the disease currently have a median survival of 56 years, whereas those with classic CF have a median survival of ~37 years, with the most common cause of death being respiratory failure. 1 Although CF is most prevalent in Caucasians (1 in 2,500), it is a panethnic disease in North America, found in all races, including African-American (1 in 15,000), Hispanic-American (1 in 13,500), and Asian-American (1 in 35,000) individuals.…”

“…1,4 Individuals with a mild form of the disease currently have a median survival of 56 years, whereas those with classic CF have a median survival of ~37 years, with the most common cause of death being respiratory failure. 1 Although CF is most prevalent in Caucasians (1 in 2,500), it is a panethnic disease in North America, found in all races, including African-American (1 in 15,000), Hispanic-American (1 in 13,500), and Asian-American (1 in 35,000) individuals. 5,6 This reflects the heterogeneity of the North American population.…”

Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

“…ystic fibrosis (CF) is a life-shortening, autosomal recessive genetic condition caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein (21,25,31). Abnormal CFTR function in the lung results in thick, viscous secretions which are difficult to clear, and this in turn leads to chronic infection, decline in lung function, and eventually respiratory failure (25).…”

Orta ve ağır akciğer tutulumu olan kistik fibrozlu hastalarda ölüme etki eden diğer risk etmenleri

“…Currently, 1910 mutations which cause CF have been defined (3). The most common mutation is F508del mutation and its frequency ranges between 30% and 80% according to the ethnic origin (4,5,6). In Turkey, the frequency of F508del mutation is 20.4%-28.4% (7,8,9,10).…”