title: SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis.
abstract: Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Rondell P
authors: RP
authors: Graham
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Michelle A
authors: MA
authors: Dina
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Sarah C
authors: SC
authors: Howe
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Malinda L
authors: ML
authors: Butz
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Kurt S
authors: KS
authors: Willkomm
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: David L
authors: DL
authors: Murray
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Melissa R
authors: MR
authors: Snyder
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota.
authors: Kandelaria M
authors: KM
authors: Rumilla
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Kevin C
authors: KC
authors: Halling
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota. Electronic address: highsmith.w@mayo.edu.
authors: W Edward
authors: WE
authors: Highsmith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D057210:Delayed Diagnosis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011446:Prospective Studies; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin