From the Guidelines
Low penetrance CFTR mutations can cause a range of milder symptoms, including recurrent sinusitis, nasal polyps, chronic cough, bronchiectasis, and recurrent respiratory infections, as well as mild digestive issues and male infertility due to congenital bilateral absence of the vas deferens (CBAVD). These symptoms are often less severe than those experienced by individuals with classic cystic fibrosis, and may not be diagnosed until adulthood 1. Some common symptoms of low penetrance CFTR mutations include:
- Recurrent sinusitis
- Nasal polyps
- Chronic cough
- Bronchiectasis
- Recurrent respiratory infections
- Mild digestive issues, such as occasional abdominal pain or constipation
- Male infertility due to CBAVD Patients with low penetrance mutations may have borderline or mildly elevated sweat chloride levels (40-60 mmol/L), rather than the higher levels seen in classic CF 1. The milder presentation of low penetrance CFTR mutations occurs because these mutations allow for some residual CFTR protein function, unlike severe mutations that completely eliminate protein function. It is essential to consider CFTR-related disorders in adults with recurrent respiratory issues or unexplained bronchiectasis, as they may not be diagnosed until adulthood 1.
From the Research
Symptoms of Low Penetrance CFTR Mutation
The symptoms of low penetrance CFTR mutation can vary, but some common manifestations include:
- Mild or single-organ system manifestations of CFTR-related disease 2
- Monosymptomatic or adult-onset diseases, called CFTR-related disorders 3
- Alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations 4
- Acquired CFTR dysfunction, which can contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis, and bronchiectasis 5
CFTR Mutation Classification
CFTR mutations can be classified into different classes based on their clinical consequences and effect on the structure and function of the CFTR channel 6. This classification is essential in the establishment of mutation-targeted therapeutic strategies. The classification of CFTR mutations includes:
- Severe variants associated with a typical multi-organ form of cystic fibrosis
- Mild variants involved in monosymptomatic or adult-onset diseases, called CFTR-related disorders 3
- Complex disease alleles and modifier genes that can influence the disease phenotype 4
Genotype-Phenotype Correlation
The correlation between CFTR genotype and disease phenotype is still not well understood 4. While a connection between CFTR genotype and disease manifested in the pancreas has been well described, pulmonary disease appears to be highly variable even between individuals with the same genotype. Further research is needed to understand the relationship between CFTR genotype and disease phenotype.