Alpha-1-antitrypsin molecular testing in Canada: A seven year, multi-centre comparison

Andre Mattman; Brian M Gilfix; Sharon Xuehui Chen; Mari L DeMarco; Barry D Kyle; Michelle L Parker; Terence A Agbor; Benjamin Jung; Shamini Selvarajah; Vilte E Barakauskas; Andrea K Vaags; Mathew P Estey; Tanya N Nelson; Marsha D Speevak

doi:10.1016/j.clinbiochem.2020.05.001

Alpha-1-antitrypsin molecular testing in Canada: A seven year, multi-centre comparison

Clin Biochem. 2020 Jul:81:27-33. doi: 10.1016/j.clinbiochem.2020.05.001. Epub 2020 May 6.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada. Electronic address: amattman@providencehealth.bc.ca.
² Department of Clinical Laboratory Medicine, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada. Electronic address: Brian.gilfix@mcgill.ca.
³ Department of Pathology and Laboratory Medicine, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
⁴ Department of Pathology and Laboratory Medicine, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada; Centre for Heart Lung Innovation, University of British Columbia, BC V6Z 1Y6, Canada. Electronic address: mdmrco@mail.ubc.ca.
⁵ DynaLIFE Medical Labs, 200, 10150 102 St, Edmonton, AB T5J 5E2, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.02 Walter C, Mackenzie Health Sciences Centre, Edmonton, AB T6G 2R7, Canada. Electronic address: barry.kyle@dynalife.ca.
⁶ DynaLIFE Medical Labs, 200, 10150 102 St, Edmonton, AB T5J 5E2, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.02 Walter C, Mackenzie Health Sciences Centre, Edmonton, AB T6G 2R7, Canada. Electronic address: michelle.parker@dynalife.ca.
⁷ DynaLIFE Medical Labs, 200, 10150 102 St, Edmonton, AB T5J 5E2, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.02 Walter C, Mackenzie Health Sciences Centre, Edmonton, AB T6G 2R7, Canada. Electronic address: terence.agbor@dynalife.ca.
⁸ Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada; Department of Pathology and Laboratory Medicine, BC Children's & BC Women's Hospitals, Children's and Women's Health Centre of British Columbia, 4480 Oak Street, Room 2J10 Vancouver, BC V6H 3V4, Canada. Electronic address: benjamin.jung@Sickkids.ca.
⁹ Department of Laboratory Medicine and Genetics, Trillium Health Partners, 2200 Eglinton Ave West, Mississauga, ON L5M 2N1, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
¹⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada; Department of Pathology and Laboratory Medicine, BC Children's & BC Women's Hospitals, Children's and Women's Health Centre of British Columbia, 4480 Oak Street, Room 2J10 Vancouver, BC V6H 3V4, Canada. Electronic address: vilte.barakauskas@cw.bc.ca.
¹¹ Department of Laboratory Medicine and Genetics, Trillium Health Partners, 2200 Eglinton Ave West, Mississauga, ON L5M 2N1, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: andrea.vaags@thp.ca.
¹² DynaLIFE Medical Labs, 200, 10150 102 St, Edmonton, AB T5J 5E2, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.02 Walter C, Mackenzie Health Sciences Centre, Edmonton, AB T6G 2R7, Canada. Electronic address: mathew.estey@dynalife.ca.
¹³ Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada; Department of Pathology and Laboratory Medicine, BC Children's & BC Women's Hospitals, Children's and Women's Health Centre of British Columbia, 4480 Oak Street, Room 2J10 Vancouver, BC V6H 3V4, Canada.
¹⁴ Department of Laboratory Medicine and Genetics, Trillium Health Partners, 2200 Eglinton Ave West, Mississauga, ON L5M 2N1, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: marsha.speevak@thp.ca.

PMID: 32387440
DOI: 10.1016/j.clinbiochem.2020.05.001

Abstract

Background: Laboratory confirmation of alpha-1-antitrypsin (A1AT) deficiency may be achieved by multiple methods. Here, we compare the relative comprehensiveness and efficiency of pathogenic variant (PV) detection of four different protocols utilized at different diagnostic centres in Canada.

Methods: Diagnostic results from 2011 to 2018 at clinical laboratories in British Columbia (BC), Alberta (AB), Ontario (ON), and Québec (QC) were reviewed. The four labs utilize the following protocols: BC-CGID (serum A1AT Concentration/Genotyping/Isoelectric focussing (IEF)/SERPINA1 DNA sequencing), AB-CID (serum A1AT Concentration/IEF/DNA sequencing), ON-CD (serum A1AT Concentration/DNA sequencing), and QC-G (Genotyping). As the respective catchment areas varied in size and ethnic composition, the comprehensiveness of PV detection was assessed by comparing the frequency of individual genotypes to the ZZ genotype, which is clearly identified by all protocols.

Results: Collectively 5399 index patients were tested identifying 396 ZZ genotypes. Serum A1AT concentration as a determinant of further testing efficiently identified PV. ON-CD had the highest detection rate for PV; genotypes with at least one PV, other than S, Z or F, were identified at 0.67/ZZ as compared to <0.2/ZZ (all others). However, ON-CD had the highest rates of undefined molecular variants (UMV) (0.16/ZZ) or likely benign variants (LBV) (0.08/ZZ), compared to all others (<0.12/ZZ and < 0.06/ZZ, respectively). The F variant was identified at 0.10/ZZ, only in the ON-CD and the AB-CID protocols. Collectively, M_Malton was the next most common variant, identified as a compound heterozygous genotype at 0.04/ZZ, only in the ON-CD and BC-CGID protocols.

Conclusion: Strategies which readily detect variants across the full coding sequence of SERPINA1 detect more PV as well as more UMV and LBV.

Keywords: A1AT deficiency; Alpha-1-antitrypsin; Diagnostic yield; Gene sequencing; Isoelectric focussing; Targeted genotyping.

Publication types

Comparative Study
Multicenter Study

MeSH terms

Canada / epidemiology
Genotype
Heterozygote*
Humans
Molecular Diagnostic Techniques / standards*
Mutation*
Phenotype
Retrospective Studies
Sequence Analysis, DNA / methods*
alpha 1-Antitrypsin / blood
alpha 1-Antitrypsin / genetics*
alpha 1-Antitrypsin Deficiency / diagnosis*
alpha 1-Antitrypsin Deficiency / epidemiology
alpha 1-Antitrypsin Deficiency / genetics

Substances

SERPINA1 protein, human
alpha 1-Antitrypsin