How is AAT Deficiency Inherited?

Common genotypes of AAT deficiency

AAT deficiency is an autosomal codominant condition, so both copies of the inherited alleles are expressed.1,2 More than 150 different variants have been identified in the SERPINA1 gene.2 The normal version (allele) of the gene is termed M.1,2 The predominant alleles associated with AAT deficiency are the Z and S alleles, with Z by far the most common, accounting for ~95% of AAT deficiency cases.1,2

  • The Z allele is associated with very low serum levels of AAT (~10%-15% of normal levels), and patients who are homozygous (ZZ) are at high risk of developing severe AAT deficiency1,2
  • The S allele is associated with moderately low serum levels of AAT2,3
  • Heterozygous patients with one S allele and one Z allele, (SZ), are also considered at increased risk for developing COPD, especially if they have ever smoked2,3
  • More than 29 million Americans are thought to have at least 1 deficient allele (S or Z) that causes alpha-1 and may pass that gene on to their children4

Other rarer variants, called null variants, are associated with the complete absence of AAT protein in the bloodstream as none is produced.2,3

Summary of the most common genotypes, AAT serum levels, and risk for AAT deficiency3:

Inherited Genetic Variants

MM
AAT Serum Level

Normal

Risk of AAT deficiency

None to Low*

ZZ
AAT Serum Level

Very Low

Risk of AAT deficiency

High

MZ (carrier)
AAT Serum Level

Moderate

Risk of AAT deficiency

Low to Moderate

SZ
AAT Serum Level

Low

Risk of AAT deficiency

Moderate to High

Null
AAT Serum Level

None

Risk of AAT deficiency

High

[Adapted from Silverman, N Engl J Med.]3

* M allele means that none of the 14 allelic variants interrogated by the AlphaID Genotyping test are detected in the SERPINA1 gene, but other variants could be present.

[Adapted from Silverman, N Engl J Med.]3

* M allele means that none of the 14 allelic variants interrogated by the AlphaID Genotyping test are detected in the SERPINA1 gene, but other variants could be present.
Inherited Genetic Variants AAT Serum Level Risk of AAT deficiency

MM

Normal

None to Low*

ZZ

Very Low

High

MZ (carrier)

Moderate

Low to Moderate

SZ

Low

Moderate to High

Null

None

High

Examine all the genetic variants detected by AlphaID™ by downloading the 14 Genetic Variants Brochure

Alpha 1 antitrypsin deficiency inheritance family tree based on an actual family.

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PI, protease inhibitor.

References:

  1. Stoller JK, Aboussouan LS. A review of alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259.
  2. National Organization for Rare Disorders. Alpha-1 antitrypsin deficiency. https://rarediseases.org/rare-diseases/alpha-1-antitrypsin-deficiency/. Accessed July 21, 2021.
  3. Silverman EK, Sandhaus RA. Clinical Practice. Alpha-1 antitrypsin deficiency. N Engl J Med. 2009;360(26):2749-2757.
  4. de Serres FJ, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64(5):382-397.
  5. Data on file, Alpha-1 Genetics Laboratory, Grifols.
  6. 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;168(7):818-900.