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Cystic fibrosis

Clinical aspects

The cystic fibrosis (CF) or mucoviscidosis is a genetic, chronic, developmental disease and it hit one newborn on 

apparati colpiti fibrosi cistica
Fig.1- Organs and systems involved in CF

2500-2700 live births. In affected individuals, a biological fluids (mucus, sweat, spit, semen, digestive fluid) secreted by exocrine glands are much more dense and viscous than normal. The most frequent (Fig.1) clinical conditions interest a respiratory tract (chronic bronchitis), pancreas (digestive problems), rarely the intestine (stercorale perforation), of the liver (cirrhosis) and reproductive system (infertility, especially in male individuals). Abnormal secretions cause a progressive damage to involved organs.
The disease occurs especially within the first few years of life, sometimes later, and it can express with greater or lesser seriousness in different individuals.
There is a only symptomatic treatment and it consists in a bronchial drainage, in the respiratory infection antibiotics giving, exams to evaluate the pancreas function, in the vitamins supplements giving for digestive and nutritional problems. In the last few years the progress and prognosis of cystic fibrosis are significantly improved, especially if the disease is diagnosed before its time.
There are also atypical disease forms, characterized by a pancreatic sufficiency and simple respiratory problems;sometimes the disease can affect exclusively one organ as in the case of male infertility or occur in both sexes, with cyclic pancreatitis.

Genetic aspects

Cystic fibrosis is a monogenic disease, transmitted as an autosomal recessive disorder caused by mutations, DNA alterations occurring in the CFTR gene (Cystic Fibrosis Transmembrane Regulator). The frequency of the healthy carriers (asymptomatic carriers) in the general population is about 1 on 25 individuals. Two healthy carrier parents will have a 25% probability to have children with cystic fibrosis.
Themselves children will have 50% probability of being healthy carriers, as their parents.
The CFTR gene produces a protein controlling the transport of salts through the cell membrane; a mutation causes an abnormal protein that modifies the salt composition of glandular secretions, becaming a dense and viscous.

Genetic test

The only way to identify healthy carriers is to perform a DNA test for CFTR gene mutations. The analysis is complicated because there are over 1900 mutations. Generally, the first level genetic test allows to identify the 77-80% of mutations, chosen from the most frequent in the geographic area of interest. In the population the most frequent mutation is the F508del (51% in Italy).There are three types of results:
• one copy of the CFTR gene is mutated, while the other copy is normal, so this individual is heterozygous for the mutation, and he is a healthy carrier, asymptomatic;

• both copies of the CFTR gene are mutated, so this individual is a compound heterozygous if there are two different mutations or omozygous if there are two same mutations and he is affected from cystic fibrosis;

• absence of mutations in the CFTR gene. This "negative" result for analyzed mutations means that an individual has a minor probability to be a carrier. The genetic test not keep out the possibility of being a carrier, because it is not possible to exclude the presence of another numerous mutations in the cystic fibrosis gene, not included in the Panel of analyzed mutations.

It's important to remember that:
• the probability of being a cystic fibrosis carrier is greater for an individual that has a carrier or affected family member. In this case it’s necessary to first identify the mutation of affected or carrier family member and then to search in relative. If the relative is not mutated, he has a very low probability to be a carrier;
• the probability of being a cystic fibrosis carrier is less for an individual that hasn’t a carrier or affected family member. In this case, if DNA test is negative, the probability of being carrier is very low, even though it isn’t zero.

Polymorphism IVS8-poly-T

In a region of the CFTR gene, called 8 intron, there is a short sequence, poly-T, formed by the succession of a nucleobase: thymine (T). The T number controls the maturation of messenger RNA and produces CFTR protein;it is subject to individual variability, so it is considered a polymorphism. T can be repeated 5, 7 or 9 times. Several studies carried out, have establised that the poly-T 5T is associated with a reduced amount of protein. Poly-T 5T and a CFTR gene mutation can cause atypical forms of cystic fibrosis, for example in males mono or bilateral agenesis of the vas deferens (CAVD) and subsequent infertility.

Genetic counseling

Tecnobios Prenatale Eurogenlab laboratory, gives a genetic counseling service to inform patients and parents, in a clear terms about the risk of disease transmission within the family, on the possibilities of diagnosis and pre-and postnatal treatment.

Response times

The result of the analysis (genetic test, level 50 mutations) is available after 10 days from the draw blood. If there is an increased risk (family, ultrasound abnormalities, etc ...) the result is available after a few days from the draw blood.
Thanks to the partnership with other centers in our laboratory is possible to extend the study to other mutation (300 mutations) and/or perform the sequencing of the coding region of all CFTR gene.

Analyzed material

DNA extracted from peripheral blood lymphocytes (in tubes with EDTA), chorionic villi, amniotic fluid.

References
Malattie genetiche – Cao, Dalla Piccola, Notarangelo – Piccin (2004)
Genetica medica essenziale – Dalla Piccola, Novelli – Il Minotauro (2006)