Verification of AATD diagnosis relies on identification of biallelic pathogenic variants in SERPINA1.
Family studies indicated recessive inheritance of antitrypsin deficiency, which means two pathogenic alleles (risk alleles) are needed to cause the symptoms. “At risk” alleles are divided into 'deficiency' and 'null' alleles.
The most common AAT deficiency allele is the Z allele. The homozygous ZZ phenotype is associated with a high risk of both emphysema and liver disease.
Another common AAT deficiency allele is the S allele. Pi*S homozygotes are at no risk of emphysema, but compound heterozygotes with a Z or a null allele have a mildly increased risk. It is not associated with liver disease.
Other rare deficiency AAT alleles may result in increased risk for both liver and lung disease (e.g., Pi M(Malton) or only emphysema (e.g., Pi M(Procida). Some rare deficiency alleles have been found in Japanese (e.g., Pi S(Iiyama).
Serum AAT level measurement is unreliable for carrier status due to an overlap in levels with normal serum ranges and acute-phase reactant effects, which may lead to diagnostic confounding.