title: Sanger sequencing solved a cryptic case of severe alpha₁-antitrypsin deficiency.
abstract: OBJECTIVE
  Alpha(1)-antitrypsin deficiency (AATD) is a clinically under-diagnosed genetic disorder that originates from deleterious mutations in the alpha(1)-antitrypsin (AAT) gene, SERPINA1. Severe deficiency is associated with significant pulmonary and hepatic malfunctions. Conventional clinical diagnosis involves the evaluation of serum AAT level and detection of diseased protein isoforms. In this communication, we describe the investigations of a case of severe AATD in which the AAT levels were well below those expected from the MZ phenotype determined by isoelectric focusing for protease inhibitor type (IEF PI-typing).
  
  
  METHODS
  In addition to the traditional diagnostic method that combines the assessment of serum AAT concentration and IEF PI-typing, we investigated the SERPINA1 gene of the proband and participating family members for mutations using Sanger sequencing.
  
  
  RESULTS
  We identified a novel mutation (M409T) in the proband, initially missed by the standard diagnostic approach. The novel mutation was present in 4 out of 8 family members who participated in the study.
  
  
  CONCLUSIONS
  This report illustrates the diagnostic value of incorporating exon sequencing of the AAT gene into the algorithm for evaluating AATD, particularly when the AAT serum level is significantly lower than expected from IEF PI-typing.
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shing H
authors.initials: SH
authors.lastname: Zhan
authors.forename: Raja T
authors.initials: RT
authors.lastname: Abboud
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jung
authors.forename: Brian
authors.initials: B
authors.lastname: Kuchinka
authors.forename: Diana
authors.initials: D
authors.lastname: Ralston
authors.forename: Brett
authors.initials: B
authors.lastname: Casey
authors.forename: Andre
authors.initials: A
authors.lastname: Mattman
mesh_terms: D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D029424:Pulmonary Disease, Chronic Obstructive / Q000000981:diagnostic imaging / Q000209:etiology; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging / Q000209:etiology; D011859:Radiography; D017422:Sequence Analysis, DNA; D000515:alpha 1-Antitrypsin / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin