Alpha-1-Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency is a relatively common genetic disorder that causes a predisposition to lung and liver disease.  Early awareness of this is essential to allow people to make lifestyle and treatment decisions to reduce their risk of serious health complications.  We offer full gene sequencing of the gene that causes AAT deficiency, in order to empower patients and their healthcare providers to make those important decisions and plan their healthcare.   

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Alpha-1 antitrypsin (AAT) deficiency is a relatively common genetic disorder that causes a predisposition to lung and liver disease.  Early awareness of this is essential to allow people to make lifestyle and treatment decisions to reduce their risk of serious health complications.  We offer full gene sequencing of the gene that causes AAT deficiency, in order to empower patients and their healthcare providers to make those important decisions and plan their healthcare.   

Disease Name 
Alpha-1 antitrypsin deficiency
A1AT deficiency
Disease Information 

Alpha-1 antitrypsin (AAT) deficiency is a relatively common genetic disorder predisposing people to respiratory and hepatic (liver) disease.  AAT deficiency is one of the most common metabolic disorders in Caucasians, occurring in approximately 1 in 5,000-7,000 people in North America.  AAT deficiency occurs in lower frequencies in all racial subgroups worldwide.1,2  Lung disease typically occurs in adulthood, but liver disease may occur from infancy to adulthood.1,2  The severity of symptoms is dependent upon the type of mutation(s) a person has.  Alpha-1 antitrypsin is the protein product of the gene SERPINA1.  AAT deficiency has co-dominant inheritance, with each copy of a person’s gene (allele) contributing individually to his/her phenotype. The alleles for SERPINA1 are named in a unique way, since these variations were identified prior to awareness of the SERPINA1 gene.  Alleles are named with a protease inhibitor or “PI” type. The most common (and normal) allele is PI*M.  The most common severe disease-causing allele is PI*Z.  Another common allele is the PI*S allele, associated with disease susceptibility (see diagram below).

Patients with the most common, severe form of AAT deficiency have two copies of the Z alleles (or PI*Z/PI*Z).  They are at increased risk for neonatal cholestasis and jaundice, juvenile or adult cirrhosis (sometimes requiring liver transplant) and chronic obstructive pulmonary disease (COPD) including early-onset emphysema.  Less frequent complications include cancer of the liver, inflammation of the fatty layer of the skin (panniculitis), and inflammation of the blood vessels (vasculitis).1,2  Smoking can substantially increase risk of lung disease.  The less severe PI*S allele causes reduced levels of AAT, while null alleles (PI*Z) produce little or no protein. Either the PI*S or PI*Z alleles may cause symptoms when present in combination with another severe deficiency allele.

While not all with AAT deficiency will have clinically significant symptoms, the condition is considered widely under-recognized.1-3  Over 300,000 people in the U.S. and Canada are estimated to have PI*SZ or PI*ZZ phenotypes.4 In these countries, approximately 1/44 people is a carrier of the Z allele and 1/17 carry the S allele.4

More than 100 variants in the SERPENA1 gene have been described, with over one third of those known to cause abnormal protein expression.3 Rare genetic variants are responsible for approximately 5% of all AAT deficiency cases.1 Full sequencing can detect both the common and rare variants within the SERPINA1 gene.

Testing Benefits & Indication 

Routine serum protein measurement of AAT and PI type testing of serum with polyacrylamide isoelectric focusing (PIEF) are often adequate for diagnosis.

The American Thoracic Society and the European Respiratory Society have published evidence-based recommendations for AAT deficiency genetic testing in select individuals for diagnostic confirmation, and to help direct medical care for those at increased risk due to family history or environmental exposures.3 This information may also be helpful for lifestyle adjustments (like smoking cessation).

Ambry’s gene sequence analysis for AAT deficiency is a valuable addition to biochemical tests. It may be offered for:

  • Resolving discrepancies and ambiguities between clinical presentation, protein measurement, and/or diagnostic confirmation
  • Testing for relatives of patients with known mutations
Test Description 

Full gene sequence analysis is performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for each exon, plus at least 5 bases into the 5’ and 3’ ends of all the introns.

Mutation Detection Rate 

The clinical sensitivity of this test is dependent on variable factors such as age or family history.5   Ambry's testing can detect >99.9% of described mutations in the SERPINA1 gene, when present (analytical sensitivity).

Specimen Requirements 

Complete specimen requirements are available here* or by downloading the PDF found above on this page.

*Blood spots not accepted for this test.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME
1140  SERPINA1 Gene Sequence Analysis                                 14-28 days

 

Specialty 
Genes 
SERPINA1
Techniques 
References 
  1. World Health Organization. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415. 
     
  2. Stoller JK, et al. Alpha-1 Antitrypsin Deficiency.  GeneReviews. 2014. Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2014.
      
  3. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med.  2003 Oct 1;168(7):818-900.
     
  4. deSerres FJ. Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest.  2002 Nov;122(5):1818-29. 
     
  5. Janciauskiene S, et al.  Clinical utility gene card for: α-1-antitrypsin deficiency.  Eur J Hum Genet. 2011 May;19(5).