Alpha-1 Antitrypsin Deficiency via the SERPINA1 Gene

Alpha-1 antitrypsin deficiency primarily affects the lungs and liver (Crystal 1990; Stockley et al. 2014). Patients commonly develop lung disease by the third to fourth decade, which is characterized by emphysema including difficulty breathing, a hacking cough and a barrel-shaped chest. Liver disease is less common, and presents with jaundice and cholestasis in children and cirrhosis in adults. In some rare cases, patients can develop a skin condition called panniculitis. Onset age and severity of different signs and symptoms vary greatly among patients depending in part on genotype.

Alpha-1 antitrypsin deficiency is an autosomal recessive disorder caused by SERPINA1 pathogenic variants (Medicina et al. 2009; Ferrarotti et al. 2014). The SERPINA1 gene has 4 coding exons that encode alpha-1-antitrypsin (AAT), also known as protease inhibitor (PI), a major plasma serine protease inhibitor. Genetic defects of SERPINA1 found to date include missense, nonsense, splicing mutations, and small and large deletions (Human Gene Mutation Database).

Detection rate of pathogenic variants in the SERPINA1 gene in a large cohort of patients with alpha-1 antitrypsin deficiency is unknown in the literature because only a limited number of cases have been reported, but is expected to be high via Sanger sequencing since large deletions appear to be rare. SERPINA1 is the only gene known to be involved in this disorder.

This test provides full coverage of all coding exons of the SERPINA1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.