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Cystic Fibrosis Screen

Cystic Fibrosis Screen

Test Summary

Cystic Fibrosis Screen

  

Clinical Use

Cystic Fibrosis
 Test Selection Guide

  • Detect cystic fibrosis (CF) carriers

  • Determine a couple’s risk of having a child with CF

  • Identify familial mutations in affected individuals

  • Diagnose CF postnatally

Clinical Background

CF is one of the most common autosomal recessive diseases affecting Caucasians, with an incidence of approximately 1 in 3,000 births and a carrier rate of 1 in 25 in this population.1,2 It also occurs in other ethnic groups at a lower frequency. The disorder may be characterized by pulmonary disease, pancreatic insufficiency, liver disease, and congenital bilateral absence of the vas deferens (CBAVD) leading to male infertility.1 Median predicted survival for CF patients is approximately 37 years,3 with lung damage causing the majority of deaths.2 A diagnosis of CF is confirmed by a positive sweat chloride test and/or detection of a CF-associated mutation on both chromosomes.1

CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of chromosome 7 (7q31.2).1 Mutations result in a defective CFTR protein that, in turn, results in defective cellular chloride transport. Over 1,900 mutations, most of which occur at frequencies of <0.1%, have been identified.4 But one mutation, F508del (delta F508), accounts for approximately 70% of all CFTR mutations in many, but not all, ethnic groups.1,4 In 2011, almost 86% of patients in the Cystic Fibrosis Foundation patient registry were reported to have at least 1 copy of F508del, and 47% had 2 copies.3

The American College of Medical Genetics (ACMG) and the American Congress of Obstetricians and Gynecologists (ACOG) recommend screening for 23 common CFTR mutations that were chosen primarily based on their frequency in Ashkenazi Jewish and non-Hispanic Caucasian populations. CF is more common in these ethnic groups, and the 23 mutations account for 94% of mutant alleles in Ashkenazi Jews and 88% in non-Hispanic Caucasians.1,2 Although the 23 mutations account for a lower percentage of mutant alleles in other ethnicities, ACMG and ACOG consider the panel of mutations pan-ethnic and recommend offering screening to all patients.1,2 This test includes the 23 ACMG/ACOG-recommended mutations and 9 other multiethnic mutations.

Individuals Suitable for Testing

  • Individuals with a family history of CF or CFTR mutations

  • Symptomatic children and adults

  • Males with CBAVD

  • Patients with chronic or idiopathic pancreatitis

  • Reproductively active individuals or couples

Method

  • Amplification of selected regions of the CFTR gene, followed by detection of wild-type and mutant sequences

  • Includes the 23 most common CF mutations as recommended by ACMG and ACOG; also includes 9 other mutations that occur at low frequency5 (Table 1)

  • Report form specifies mutations screened, mutations identified, and interpretive information

Table 1. CF Mutations and Polymorphisms Detected

Conventional

Name

HGVS cDNA

Nomenclature

Conventional

Name

HGVS cDNA

Nomenclature

394delTT c.262_263delTT

G85Ea

c.254G>A

621+1G>Ta

c.489+1G>T

G542Xa

c.1624G>T

711+1G>Ta

c.579+1G>T

G551Da

c.1652G>A
1078delT c.948delT

I507dela,b

c.1519_1521delATC

1717-1G>Aa

c.1585-1G>A

N1303Ka

c.3909C>G

1898+1G>Aa

c.1766+1G>A

R117Ha,b

c.350G>A
2183AA>G c.2051_2052delAAinsG

R334Wa

c.1000C>T

2184delAa

c.2052delA

R347H

c.1040G>A

2789+5G>Aa

c.2657+5G>A

R347Pa

c.1040G>C

3120+1G>Aa

c.2988+1G>A

R553Xa

c.1657C>T

3659delCa

c.3528delC

R560Ta

c.1679G>C

3849+10kbC>Ta

c.3717+12191C>T

R1162Xa

c.3484C>T
3876delA c.3744delA

S549N

c.1646G>A
3905insT c.3773_3774insT

S549R

c.1645A>C or
c.1647T>G

A455Ea

c.1364C>A

V520F

c.1558G>T

F508dela,b

c.1521_1523delCTT

W1282Xa

c.3846G>A
HGVS, Human Genome Variation Society
a ACMG/ACOG-recommended mutation.1
b The variants 5T/7T/9T, I506V (c.1516A>G), and I507V (c.1519A>G) are included as needed (see Interpretive Information). 5T/7T/9T may be of clinical significance in congenital bilateral absence of the vas deferens (CBAVD) and other disorders.

Interpretive Information

The following information will help with interpretation of test results. Additional assistance is available from our Genetic Counselors by calling 866-GENE-INFO (866-436-3463).

Diagnosis

Detection of 2 mutant alleles in conjunction with positive clinical findings or family history is consistent with CF. Failure to detect 2 mutant alleles in a symptomatic patient, however, does not exclude a diagnosis of CF. Not all individuals with CF will have 2 mutations identified by this test. Sweat chloride testing should be performed in all suspected CF cases.

Carrier Detection

The presence of a single CF mutation in an asymptomatic individual identifies that person as a carrier. As shown in Table 2 below, absence of a CF mutation significantly reduces, but does not eliminate, the risk of being a carrier. The residual risk of being a carrier (ie, of having a CF mutation not screened for in this assay) is influenced by the individual’s ethnicity and clinical and family history. If clinically indicated, additional testing is available. 

 

Table 2. CF Carrier Risk Based on a Negative CF Screen and Ethnicitya,b
Ethnicity Detection Rate, % Prior Risk Approximate Risk
After Negative CF Screen
Ashkenazi Jewish 94 1/24 1/400
Non-Hispanic Caucasian 88 1/25 1/208
Hispanic American 72 1/46 1/164
African American 65 1/65 1/186
Asian American 49 1/94 1/184

a Detection rates and residual risk estimates are based on the 23 ACMG/ACOG-recommended mutations.6 Exact figures are unavailable for this panel, but because the panel tests more mutations, detection rates may be slightly higher and risk rates after a negative CF screen may be slightly lower than the figures in this table.
b Risks are based on the assumption that there is no family history of CF.

IVS8 5T/7T/9T Variant  

  • A single 5T variant with an R117H mutation on the same chromosome (in cis) acts as a classic CF mutation. Thus, an individual with this genotype is a CF carrier.1 A 5T variant occurring in trans (on the opposite chromosome) with an R117H mutation may result in CBAVD.1

  • A 7T or 9T variant in cis with an R117H mutation acts as a mild CF mutation.1 Thus, an individual with this genotype is a CF carrier. When coupled with a classic CF mutation, male patients may have CBAVD.

Identification of an R117H mutation is followed by testing for the 5T/7T/9T variant in intron 8. If a 5T variant is identified, testing of family members is required to determine if the variant is in cis or trans.1 Genetic counseling is recommended.

I506V and I507V Variants

  • I506V and I507V are not associated with CF or CBAVD.

  • Individuals who are heterozygous for an I507del (delta I507) or F508del (delta F508) mutation and have an I506V or I507V variant on the other chromosome appear to be homozygous on many CF detection assays (ie, carriers may be misclassified as CF-affected individuals). Thus, when results indicate an I507del or F508del homozygote, testing for I506V and I507V is performed to rule out a false-positive CF test.1

Risk Calculation for a CF-affected Fetus 

A couple’s risk of having a CF-affected fetus = [(mother’s carrier risk) (father’s carrier risk)] ÷ 4.1 This risk is the same for each pregnancy, regardless of the outcomes of prior pregnancies.

References

  1. American College of Medical Genetics. Technical standards and guidelines for CFTR mutation testing. 2006 ed. http://www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm. Updated April 26, 2006. Accessed November 21, 2013.

  2. Committee on Genetics, American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 486, April 2011. Update on carrier screening for cystic fibrosis. Obstet Gynecol. 2011;117:1028-1031.

  3. Cystic Fibrosis Foundation Patient Registry. 2011 Annual Data Report. http://www.cff.org/LivingWithCF/Quality
    Improvement/PatientRegistryReport/. Accessed November 22, 2013.

  4. Cystic Fibrosis Mutation Database. Toronto, Ontario, Canada: Cystic Fibrosis Centre at the Hospital for Sick Children. http://www.genet.sickkids.on.ca/StatisticsPage.html. Updated April 25, 2011. Accessed November 22, 2013.

  5. Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45:1160-1167.

  6. Committee on Genetics, American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 325, December 2005. Update on carrier screening for cystic fibrosis. Obstet Gynecol. 2005;106:1465-1468.

     

Content reviewed 02/2014

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