Can a carrier of the pathogenic variant c.1624G>T (p.G542*) exhibit symptoms or are they only at risk of passing it on?

Carriers of the c.1624G>T (p.G542*) CFTR Pathogenic Variant Are Typically Asymptomatic

Carriers of the c.1624G>T (p.G542) CFTR pathogenic variant typically do not exhibit symptoms and are only at risk of passing the variant to their offspring.* 1

Understanding CFTR Carrier Status

The c.1624G>T (p.G542*) variant is a well-established pathogenic variant in the CFTR gene that is included in the American College of Medical Genetics and Genomics (ACMG) recommended carrier screening panel for cystic fibrosis 1. This specific variant:

• Creates a premature stop codon (designated by the * symbol)
• Is classified as a disease-causing variant
• Is one of the 100 variants recommended for CF carrier screening

Inheritance Pattern and Carrier Status

Cystic fibrosis follows an autosomal recessive inheritance pattern, which means:

• Carriers have only one copy of the pathogenic variant
• Disease manifestation requires two pathogenic variants (one on each chromosome)
• Carriers typically do not exhibit symptoms of the disease 1

As explained in the Nature Reviews Genetics article, "For recessive diseases, two copies of the pathogenic variant must be present, or it must be in trans to another pathogenic variant, as a so-called compound heterozygote." 1

Clinical Implications for Carriers

Carriers of the G542* variant:

• Have one normal functioning copy of the CFTR gene, which is generally sufficient to prevent disease manifestation
• Have approximately a 1 in 4 chance of having a child with cystic fibrosis if their reproductive partner is also a carrier
• Should be offered genetic counseling to understand reproductive risks 2

Reproductive Considerations

For individuals identified as carriers of the G542* variant:

• Partner testing is recommended before or during pregnancy planning
• If both partners are carriers, options such as preimplantation genetic testing, prenatal diagnosis, or donor gametes may be discussed
• Genetic counseling should include discussion of autosomal recessive inheritance patterns and reproductive options 2

Special Considerations

While carriers typically do not exhibit symptoms, there are important caveats to consider:

1. Variable penetrance: Recent research suggests that some pathogenic variants may have variable effects in carriers due to polygenic backgrounds and epistatic effects 3

2. Family communication: Carriers should be encouraged to share genetic information with biological relatives who may also be at risk of being carriers 4

3. Ethnicity considerations: The G542* variant has been found at higher frequencies in certain populations, particularly those with Spanish ancestry, with a frequency of approximately 7.2% of CF chromosomes in Mexican CF patients 5

Management Recommendations for Carriers

For individuals identified as carriers of the G542* variant:

• No specific medical interventions or monitoring are required for the carrier's health
• Genetic counseling is recommended, particularly for family planning
• Testing of at-risk family members should be considered, especially siblings who have a 50% chance of also being carriers

Remember that being a carrier of a recessive condition like cystic fibrosis does not impact the individual's health but is important information for reproductive decision-making.