Alpha-1-antitrypsin deficiency secondary to SERPINA1 mutations


Variants in SERPINA1 are associated with alpha-1-antitrypsin (A1AT) deficiency, which is inherited as an autosomal recessive condition. A1AT deficiency is one of the most common genetic disorders in Caucasian populations. In North America, approximately one individual in every 5,000-7,000 has A1AT deficiency. Clinically significant alpha-1-antitrypsin deficiency is typically the result of homozygosity for the PI*Z allele or compound heterozygosity for the PI *S*Z alleles, although other disease-causing alleles are identified in ~5% of affected individuals.

A1AT deficiency is characterized by liver disease from infancy and throughout adulthood and by lung disease in adults, particularly those who smoke cigarettes. The clinical features of A1AT deficiency in the neonatal period are jaundice, pruritus, failure to thrive, and hepatosplenomegaly. In adults, A1AT deficiency results in pulmonary disease. A1AT is a serum protease inhibitor. In the adult liver, A1AT deficiency may lead to the accumulation of insoluble intracellular proteins in hepatocytes and bile ducts, leading to cirrhosis and fibrosis. However, the etiology of liver disease in children with A1AT deficiency is not well understood. In the lung, A1AT deficiency leads to a reduced inhibition of leukocyte elastase resulting in destruction of the elastin in the alveolae resulting in pulmonary disease. Hepatocellular carcinoma, panniculitis, and Wegener granulomatosis are rare complications of A1AT deficiency.

Approximately 2% of individuals with the PI *Z*Z genotype develop severe liver disease in childhood while approximately 10% of adults over 50 years of age develop cirrhosis. In contrast, pulmonary disease is very rare in children with the PI *Z*Z genotype, while adults with this genotype who smoke cigarettes have a significantly increased risk of developing chronic obstructive pulmonary disease (COPD). Heterozygotes for the Z allele are not at increased risk for liver disease, but may have a mildly increased risk of pulmonary dysfunction in adulthood, particularly among individuals who smoke. An individual’s genotype and history of environmental exposures contribute to a highly variable phenotype, even among family members.


  • Obstructive jaundice in infancy or childhood
  • Cirrhosis, fibrosis or hepatocellular carcinoma in adults
  • Chronic obstructive pulmonary disease (COPD) in adults
  • Presymptomatic testing of at-risk siblings
  • Prenatal diagnosis of at-risk pregnancies
  • Carrier testing in relative of a patient with A1AT deficiency

Testing Methodology

Genotyping: TaqMan-based genotyping assay to detect Z and S alleles only.

Gene Sequencing: PCR-based sequencing of entire coding region, intron/exon boundaries, as well as known pathogenic variants (HGMD 2018.1) in the promoter and deep intronic regions of the specified gene.

Test Sensitivity

Genotyping Assay: This test detects only the Z and S alleles which account for 95% of disease causing variants.

Gene Sequencing: The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Limitations: Variants in regulatory regions and non-reported variants in untranslated regions may not be detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events will not be identified. Rare primer site variants may lead to erroneous results.

Turnaround Time

Genotyping Assay: 2 business days

SERPINA1 full gene sequence analysis: 28 days

How to Order

Testing for this gene is available as part of the Liver Disease Panel by next-generation sequencing. Single gene sequencing, deletion/duplication analysis and targeted variant analysis is also available for this gene. Download Heritable Liver Disease requisition.


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Kidd, VJ, et al. (1983). Nature, 304(5923), 230-234.