Alpha-1-Antitrypsin Deficiency is a common genetic disorder predisposing to respiratory and hepatic disease. Patients with the most common severe form of the disease are at increased risk of neonatal cholestasis; juvenile or adult cirrhosis, sometimes requiring liver transplant; and chronic obstructive pulmonary disease including early-onset emphysema. Less frequent complications include hepatocellular carcinoma, panniculitis, and vasculitis. Smoking and environmental pollutants are known risk factors for development or worsening of AAT-related lung disease. While not all patients with AAT Deficiency will have clinically significant symptoms, the condition is considered widely under-recognized.^2.3

AAT Deficiency has codominant inheritance, with each allele contributing individually to the patient’s phenotype. Alleles are named with a protease inhibitor or “PI” type. The Z and S alleles are the two most common disease-causing variants. Patients with two copies of the Z allele present with the most severe form of the disease. Carriers of a Z allele and a normal allele, compared to PI SZ or PI ZZ individuals, appear to be at lesser but still increased risk of cirrhosis and obstructive lung disease, particularly in the presence of environmental triggers.⁶ The less severe S allele causes reduced serum levels of AAT and null alleles produce little or no protein. Either the S or a null allele may cause symptoms when present in combination with another severe deficiency allele.

AAT Deficiency affects all racial subgroups.¹ Over 300,000 people in the U.S. and Canada are estimated to have PI SZ or PI ZZ phenotypes.¹ In these countries, approximately 1/44 people are carriers of the Z allele and 1/17 carry the S allele.²

More than 100 variants in the AAT gene have been described, with over one third of those known to cause abnormal protein expression.³ Rare genetic variants are collectively not so rare, causing approximately 5% of deficiency cases.²

The Ambry Test: Alpha-1-Antitrypsin Deficiency is the most sensitive molecular genetic test available for detecting mutations in SERPINA1, the gene responsible for Alpha-1-Antitrypsin (AAT) Deficiency. With a detection rate of 99%, our full-gene analysis diagnoses the common S and Z alleles, rare variants, and most null alleles. The Ambry Test is a valuable adjunct to biochemical testing for precise diagnosis and resolution of discrepancies between clinical phenotype, serum protein measurement, and PI typing.

Biochemical testing methods cannot always differentiate the two AAT alleles or reliably diagnose variants because:

• Variants migrating close to another PI type protein or close to the usual position of a commonly-seen PI type may be misnamed.^4,5,6
• Minimally-secreted variants may not appear at a detectable level.⁵
• AAT is an acute-phase reactant and may be elevated by infection, inflammation, cancer, liver disease, and other conditions.⁷
• Chemical reactions of AAT may create artifacts and cause misreading of results, such as in the presence of liver disease or drug therapy.^7,8,9
• The use of enzyme augmentation therapy obscures native protein measurement.¹⁰
• PI*Z/PI*Null combinations can be misinterpreted as PI ZZ due to the absence of the null protein product.^7,10

The Ambry Test is a complete molecular analysis and is not subject to these limitations.

* See our Gene Report 5 for annotated references.

Clinical indiations for testing with the Ambry Test: AAT Deficiency are:

• Resolving discrepancies or ambiguities between clinical presentation, protein measurement, and/or phenotyping
• Carrier testing for relatives of patients with known mutations
• Prenatal diagnosis for carrier couples

The Ambry Test: AAT Deficiency

Gene Report 5
The Role of Full Gene Sequence Analysis in the Diagnosis of Alpha-1-Antitrypsin Deficiency
(Abobe PDF document)

General Test Information
The Ambry Test: AAT Deficiency
(Abobe PDF document)

The following CPT Codes for The Ambry Test reflects Ambry Genetics’ interpretation of CPT coding requirements based on AMA guidelines:

Ambry Test: Alpha-1-Antitrypsin (AAT)
83891, 83894, 83898, 83904, 83909, 83912

CPT codes are provided only as a guide to assist you in billing. CPT coding is the sole responsibility of the billing party.

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Disclaimer:

This test was developed and its performance characteristic were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing. Although molecular tests are highly accurate, rare diagnostic errors may occur. The Ambry Test analyzes the following types of mutations (nucleotide substitutions, small deletions, small insertions, and small indels) and is not intended to analyze the following types of mutations (gross insertions, gross deletions, gross rearrangements, and other unknown abnormalities). The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: AAT Deficiency is designed and validated to be capable of detecting ~99% of SERPINA1 mutations (considering the other ~1% to be gross abnormalities, variants in intronic regions not tested, or unknown abnormalities). AAT Deficiency is a complex clinical disorder, which in the majority of cases is due to alterations in the SERPINA1 gene generally detected by the Ambry Test: AAT Deficiency except as noted above. Mutations in other genes or non-coding regions not tested by the Ambry Test: AAT Deficiency can also give rise to clinical conditions similar or identical to AAT Deficiency. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. The report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature. References are available upon request.