What are the implications and management for a patient with a positive heterozygous Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) screen?

Approach to a Patient with Positive Heterozygous CFTR Screen

A positive heterozygous CFTR screen confirms the patient is a carrier for cystic fibrosis and requires immediate partner testing with genetic counseling, as there is a 1 in 4 risk of having an affected child if the partner is also a carrier. 1

Immediate Steps

1. Confirm the Result and Variant Details

• Verify which specific CFTR mutation was identified (e.g., ΔF508, R117H, W1282X) as this impacts counseling 1
• For R117H carriers, reflex testing for 5T/7T/9T variants must be performed to determine phenotype implications, particularly regarding congenital bilateral absence of vas deferens (CBAVD) in males 1
• For F508del or F507del carriers, confirm testing for variant codons I506V, I507V, and F508C was performed to rule out false positives 1

2. Provide Genetic Counseling

All CFTR carriers must receive genetic counseling regardless of whether they have symptoms or family history 1

Key counseling points include:

• The patient is a carrier and will not develop classic CF (assuming they are asymptomatic) 1
• Carrier status means one copy of a CF mutation was identified 1
• Risk to offspring depends entirely on partner's carrier status 1

3. Partner Testing - Critical Next Step

Immediately offer carrier testing to the reproductive partner using mutation analysis 1

• If partner tests positive (both carriers): The couple has a 25% (1 in 4) risk with each pregnancy of having a child with CF 1
• If partner tests negative: Risk is significantly reduced but not eliminated due to residual carrier risk based on ethnicity 1

Residual Risk Assessment After Negative Partner Test

Calculate residual risk based on partner's ethnicity and detection rate of the panel used: 1

• Ashkenazi Jewish: 1 in 930 (97% detection rate)
• European Caucasian: 1 in 140 (80% detection rate)
• African American: 1 in 207 (69% detection rate)
• Hispanic American: 1 in 105 (57% detection rate)
• Asian American: Limited data available (1 in 90 baseline)

These residual risks are modified upward if there is a positive family history of CF requiring Bayesian analysis 1

Special Variant Considerations

R117H Carriers Require Additional Interpretation

If R117H is detected, the 5T/7T/9T poly-T tract status determines clinical significance: 1

• R117H with 5T in cis: Associated with variable CF phenotype when compound heterozygous with another CFTR mutation 1
• R117H with 5T in trans: Relatively benign mutation associated with CBAVD in males (infertility) but not classic CF; no known clinical features in females 1
• R117H without 5T (5T negative): Not expected to cause typical CF phenotype but associated with CBAVD in males 1
• Parental testing is recommended to determine cis vs. trans configuration when R117H and 5T are both present 1

The penetrance of 5T is reduced (approximately 60%), making clinical prediction difficult 1

Family Cascade Testing

Recommend carrier testing for at-risk family members including: 1

• Siblings of the carrier
• Parents (if reproductive age or for family planning purposes)
• Extended family members of reproductive age

Reproductive Options for Carrier Couples (Both Partners Positive)

If both partners are carriers, discuss all reproductive options: 1

1. Prenatal diagnosis via chorionic villus sampling or amniocentesis
2. Preimplantation genetic testing (PGT-M) with IVF to select unaffected embryos
3. Donor gametes from non-carrier donors
4. Newborn screening only with preparation for potential affected child
5. Pregnancy avoidance

Clinical Monitoring of the Carrier Patient

Asymptomatic adult carriers discovered through screening are unlikely to develop atypical CF manifestations and do not require CF-specific monitoring 2

However, be aware that some CF carriers with otherwise unexplained conditions may have atypical presentations: 2

• Chronic pancreatitis
• Chronic rhinosinusitis
• Adult-onset pulmonary disease
• Male infertility due to CBAVD (especially with R117H or 5T variants)

These associations are influenced by other genetic and environmental factors, not carrier status alone 2

Documentation Requirements

Document in the medical record: 1

• Specific CFTR mutation identified
• Ethnicity for residual risk calculation
• Partner testing recommendation and results
• Genetic counseling provided
• Family cascade testing recommendations

Common Pitfalls to Avoid

• Never assume a negative partner test eliminates all risk - residual carrier risk remains based on panel sensitivity and ethnicity 1
• Do not overlook R117H reflex testing - failure to test for 5T/7T/9T variants leads to incomplete counseling 1
• Avoid reassuring male R117H carriers about fertility without discussing CBAVD risk 1
• Do not forget to modify residual risk calculations when family history of CF is present 1
• Never provide carrier screening results without offering genetic counseling - this is a guideline requirement 1