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Cystic Fibrosis

Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in Caucasians, with an incidence of 1 in 3300 newborns. The disease is less common in other ethnic groups.

Prevalence of Cystic Fibrosis

Ethnic Group

Carrier

Disease

European Caucasian

1:29

1:3,300

Ashkenazi Jewish

1:29

1:3,300

Hispanic American

1:46

1:8,500

African American

1:65

1:15,300

Asian American

1:90

1:32,100

Cystic fibrosis is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a protein that serves as a chloride ion channel in epithelial cell membranes. Mutations that result in defective CFTR function cause cells to be impermeable to chloride conductance, leading to increased chloride and sodium concentration in sweat and highly viscous mucus. The latter is responsible for most of the clinical and pathological effects of cystic fibrosis.

Discovery of these CFTR mutations has facilitated genetic screening for carrier status. In March 2001, the American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommended that all Caucasian couples who are pregnant or are considering pregnancy be offered carrier screening for cystic fibrosis. They also recommended that non-Caucasian couples be made aware of the availability of screening. The rationale for these recommendations is that carrier detection allows for earlier identification of at risk couples who would then have the ability to exercise their reproductive options, including prenatal diagnosis and earlier treatment of affected children.

More than 900 different mutations have been detected, but most are very rare. Only a few dozen have an allele frequency of greater than 1 in 1000 in the general population. Studies in the general Caucasian population revealed that a panel of 15 to 20 mutations detected more than 80% of carriers. Analysis of only 7 mutations detected 97% of carriers in the Ashkenazi Jewish community. Because it is not practical or cost effective to test for all 900 mutations, ACOG and ACMG has recommended that a pan-ethnic core panel of the 25 most common mutations should be used for carrier screening.

Core Mutation Panel

DF508

R117H

711+1G>T

DI507

1717-1G>A

1898+1G>A

G542X

A455E

2184delA

G551D

R560T

1078delT

W1282X

R1162X

3849+10kbC>T

N1303K

G85E

2789+5G>A

R553X

R334W

3659delC I148T

621+1G>T

R347P

3120+1G>A

The DF508 mutation accounts for 70% of cystic fibrosis cases in the Caucasian population, while the W1282X mutation is most common in Ashkenazi Jews. In general, it is not possible to predict disease severity from knowledge of the mutations. However, the highest risk of pancreatic insufficiency is associated with DF508, G542X, G551D, N1303K and W1282X mutations. The R117H mutation is associated with both cystic fibrosis and congenital bilateral atresia of the vas deferens.

Because this panel is limited, some carriers will not be detected. The detection rate of this panel varies with ethnicity. The following table lists the detection rate of the panel and the remaining carrier risk for an individual who has a negative result.

Estimated Carrier Risk

Ethnic Group

Detection Rate (%)

Risk before

Test

Risk after negative test

European Caucasian

80

1:29

1:140

Ashkenazi Jewish

97

1:29

1:930

Hispanic American

57

1:46

1:105

African American

69

1:65

1:207

Asian American

30

1:90

1:125

Screening may be performed either before pregnancy or during the first trimester. Preconception screening is preferable. Screening of both partners can be accomplished either concurrently or sequentially. Concurrent screening of both partners is recommended for Caucasians and Ashkenazi Jews. This provides a more rapid and precise estimate of carrier status and the risk of cystic fibrosis in their offspring. Sequential screening is the screening of one partner followed by screening of the second partner only in the event of a positive result in the first partner. Since most individuals test negative, this strategy is less expensive but takes longer. Also, since the screening tests are not 100% sensitive, there is a higher residual risk when only one partner is tested and found to be negative and the carrier status of the other partner remains unknown.

Risk of Cystic Fibrosis Affected Infant if One or Both Parents Test Negative

Ethnic Group

One Negative

Both Negative

European Caucasian

1:140

1:78,400

Ashkenazi Jewish

1:930

1:3,459,6000

Hispanic American

1:105

1:44,100

African American

1:207

1:171,396

Asian American

1:125

Unknown

Request forms must include the patient’s ethnic background and their family history of cystic fibrosis in order for the laboratory to estimate risk accurately. Specimen requirement is one lavender top (EDTA) tube of blood.

Chronic Pancreatitis & CFTR Mutations

The cystic fibrosis transmembrane conductance regulator (CFTR) gene codes for a protein that serves as a chloride ion channel in epithelial cell membranes. Mutations in this gene cause cells to be impermeable to chloride conductance, leading to increased sweat chloride concentration, highly viscous mucus and organ damage from ductal inspissation. Most patients that inherit two abnormal CFTR alleles develop cystic fibrosis with pancreatic insufficiency.

More widespread screening of individuals in recent years has led to the realization that the clinical spectrum of disease caused by CFTR mutations is much broader than originally thought. This heterogeneity is due to the more than 900 different CFTR mutations that have been identified. Approximately 2% of adults present with atypical or mono-symptomatic disease including chronic bronchitis, sinusitis with nasal polyposis, male infertility due to obstructive azoospermia or chronic pancreatitis.

Patients that have cystic fibrosis with pancreatic insufficiency generally inherit two CFTR alleles associated with severe abnormalities in chloride conductance. However, patients that inherit at least one allele associated with mild disease retain some degree of pancreatic sufficiency, but are more likely to develop chronic pancreatitis.

A study from Duke University evaluated the usefulness of CFTR genotyping in patients referred for chronic pancreatitis (NEJM 1998;339:653-8). The mean age at time of diagnosis was 36 years, with a range of 12 to 65 years. Each patient had experienced at least two episodes of pancreatitis more than 6 months apart. Patients were excluded from the study if they had other known causes of pancreatitis such as alcohol abuse, hyperlipidemia, pancreas divisum, pancreatic cancer, gallstones or medications associated with pancreatitis. Twenty seven patients were tested for 18 different mutations. None of the patients had pulmonary disease or any other diagnostic criteria suggestive of cystic fibrosis. Ten of 27 (37%) patients had at least one CFTR mutation and 3 patients had two mutations. The frequency of a single CFTR mutation was 11 times higher than the expected frequency in the general population, while the frequency of two mutations was 80 times higher than expected. The actual frequency of CFTR mutations in patients with idiopathic pancreatitis may be even higher because these patients were tested for only 18 of the 900 known mutations.

A larger study involving 134 patients detected at least 1 CFTR mutation in 13.4% of patients (NEJM 1998; 339:645-52). The detection rate was lower than in the other study because all patients with pancreatitis were tested, without first excluding those with known causes of pancreatitis.

Approximately 40% of cases of pancreatitis are considered to be idiopathic. These studies suggest that CFTR genotyping may be useful in determining the etiology of so-called idiopathic chronic pancreatitis. Patients with two mutations are especially prone to experience recurrent bouts of chronic pancreatitis. Patients with one mutation appear to be at increased risk of recurrent pancreatitis after exposure to alcohol or certain drugs.

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