USMLE Guide: Genetics of Cystic Fibrosis

Introduction

Cystic fibrosis (CF) is a genetic disorder that primarily affects the lungs, pancreas, liver, and intestines. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This USMLE guide aims to provide a comprehensive overview of the genetics of cystic fibrosis, including inheritance patterns, molecular biology, and diagnostic approaches.

Genetics and Inheritance Patterns

1. Autosomal Recessive Inheritance: CF is inherited in an autosomal recessive manner, meaning that both copies of the CFTR gene must have mutations for a person to develop the disease.
2. CFTR Gene Mutations: The CFTR gene is located on chromosome 7 and encodes a protein involved in the regulation of salt and water movement across cell membranes.
3. Delta F508 Mutation: The most common CFTR mutation is the deletion of a phenylalanine residue at position 508 (Delta F508). It accounts for approximately 70% of CF cases in the United States.
4. Other CFTR Mutations: Over 2,000 other mutations have been identified, with varying frequencies across different populations.

Molecular Biology of CF

1. CFTR Protein Dysfunction: CFTR mutations result in defective or absent CFTR protein function, leading to impaired chloride and water transport in exocrine epithelial cells.
2. Viscous Secretions: Reduced chloride and water transport results in the production of thick, viscous secretions in various organs, particularly affecting the respiratory and digestive systems.
3. Impaired Mucociliary Clearance: The abnormal secretions impair mucociliary clearance in the airways, leading to recurrent infections and chronic inflammation.
4. Pancreatic Insufficiency: In the pancreas, inadequate CFTR function affects the release of digestive enzymes, causing malabsorption and malnutrition.

Clinical Manifestations

1. Respiratory Symptoms: Chronic cough, recurrent respiratory infections, bronchiectasis, and progressive lung disease are common respiratory manifestations of CF.
2. Gastrointestinal Symptoms: Pancreatic insufficiency leads to malabsorption, steatorrhea, and nutritional deficiencies. Meconium ileus may occur in newborns.
3. Other Organ Involvement: CF can also affect the liver, causing cholestasis and biliary cirrhosis, as well as the reproductive system, leading to infertility in males due to absent vas deferens.

Diagnosis and Screening

1. Newborn Screening: CF is included in routine newborn screening programs in most countries, involving the measurement of immunoreactive trypsinogen (IRT) and subsequent CFTR mutation analysis.
2. Sweat Chloride Test: The gold standard diagnostic test for CF is the sweat chloride test, which measures the concentration of chloride in sweat. Values above 60 mmol/L are consistent with CF.
3. Genetic Testing: Genetic testing can identify specific CFTR mutations, aiding in confirmation of diagnosis and carrier screening for family members.

Management and Treatment

1. Supportive Care: Treatment focuses on managing symptoms, optimizing nutrition, and preventing complications. This includes airway clearance techniques, bronchodilators, pancreatic enzyme replacement, and nutritional supplements.
2. Lung Transplantation: In severe cases, lung transplantation may be an option for individuals with end-stage lung disease.
3. Emerging Therapies: Recent advancements in CFTR modulator therapies, such as ivacaftor, lumacaftor, and tezacaftor, have shown promising results in improving CFTR function in specific mutations.

Conclusion

Understanding the genetics of cystic fibrosis is essential for diagnosis, management, and counseling of affected individuals and their families. The autosomal recessive inheritance pattern, CFTR gene mutations, and resulting molecular biology abnormalities form the basis for the clinical manifestations and diagnostic approaches used in CF. Ongoing research and advancements in treatment options continue to improve outcomes for individuals with cystic fibrosis.