What is the recommended approach for genetic testing and management of relatives of a patient with alpha one antitrypsin deficiency?

Genetic Testing for Relatives of Patients with Alpha-1 Antitrypsin Deficiency

Genetic counseling and testing should be offered to all first-degree relatives (parents, siblings, and offspring) of individuals identified with an abnormal gene for alpha-1 antitrypsin deficiency (AATD), regardless of whether they are heterozygous or homozygous carriers. 1

Testing Recommendations by Relationship

Siblings

• Strong recommendation for testing (Type A recommendation)
• Siblings of a person with homozygous AATD (e.g., PI*ZZ) have a 25-100% chance of being homozygous themselves, depending on parental genotypes 1
• Even siblings of heterozygotes should be tested due to their 25% chance of carrying a deficient allele 1

Offspring

• Conditional recommendation for testing (Type B recommendation)
• Children of a person with homozygous AATD can only be homozygous if the other parent is at least heterozygous 1
• Children of heterozygotes have a 25% chance of inheriting the deficient allele 1
• Testing should be discussed with consideration of potential psychosocial impacts 1

Parents

• Conditional recommendation for testing (Type B recommendation)
• If the proband is homozygous, at least one or both parents must be heterozygous or homozygous 1
• Even heterozygotes may be at risk for adverse health effects 1

Distant Relatives

• Conditional recommendation for testing (Type B recommendation)
• Lower likelihood of being homozygous but still warranted due to potential health implications even for heterozygotes 1

Testing Approach

For High Clinical Suspicion Cases

(Early-onset COPD, low smoking history, family history of AATD, etc.)

1. Measure serum AAT levels
2. Perform genetic testing with DNA sequencing of the coding regions of SERPINA1 gene 1

For Moderate Clinical Suspicion Cases

1. Measure serum AAT levels first
2. If AAT level is <23mmol/L (<1.2 g/L), proceed with genetic testing with DNA sequencing 1

Important Considerations

Genetic Counseling

• Genetic counseling should accompany testing to help individuals understand:
  • Inheritance patterns
  • Disease risk
  • Implications for family planning
  • Preventive measures (smoking avoidance, occupational exposure limitation) 1

Novel Variants

• Patients with novel mutations should be referred to specialized centers with clinicians and geneticists experienced in AATD care 1
• These centers can functionally characterize novel variants and evaluate clinical implications for patients and their relatives

Nomenclature

• Both Human Genome Variation Society (HGVS) nomenclature and traditional Pi protein phenotyping nomenclature should be reported during this transition period 1
• This dual reporting ensures clarity in communication between healthcare providers

Rare Variants

• AATD extends beyond the common Z and S variants
• Comprehensive testing is needed to identify rare variants that may contribute to disease 2
• The F variant (c.739C>T; p.Arg247Cys) is the most commonly reported rare variant worldwide 2

Clinical Implications of Testing

Lung Disease

• Early detection allows for preventive measures:
  • Smoking cessation/avoidance
  • Avoidance of occupational exposures
  • Appropriate monitoring
  • Consideration of augmentation therapy when appropriate 1

Liver Disease

• Liver disease occurs primarily with Z allele and several others (e.g., S iiyama, M malton)
• Other deficiency alleles (e.g., null variants, S) generally do not predispose to liver disease 1
• Early detection allows for appropriate monitoring and management

Common Pitfalls to Avoid

1. Relying solely on serum AAT levels: Levels can be falsely elevated during inflammation (acute phase reactant) and may not detect carriers reliably in family screening settings 1

2. Limited genotyping: Testing only for common Z and S variants may miss rare variants that can cause disease 2

3. Delayed testing: Early identification allows for preventive measures before onset of disease 1

4. Inadequate counseling: Testing should be accompanied by appropriate genetic counseling to address psychosocial concerns and provide education about disease risk and prevention 1

5. Overlooking heterozygotes: Even heterozygotes may be at risk for adverse health effects and should be monitored appropriately 1

By following these recommendations, clinicians can ensure appropriate identification and management of AATD in family members of affected individuals, potentially reducing morbidity and mortality through early intervention.