加拿大的α-1-抗胰蛋白酶分子检测：一项为期七年的多中心比较研究。

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

机构信息

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.

Department of Clinical Laboratory Medicine, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.

出版信息

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

DOI:10.1016/j.clinbiochem.2020.05.001

PMID:32387440

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 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.

摘要

背景

α-1-抗胰蛋白酶（A1AT）缺乏症的实验室确认可以通过多种方法实现。在这里，我们比较了加拿大不同诊断中心使用的四种不同方案在检测致病性变异（PV）方面的相对全面性和效率。

方法

回顾了 2011 年至 2018 年不列颠哥伦比亚省（BC）、艾伯塔省（AB）、安大略省（ON）和魁北克省（QC）临床实验室的诊断结果。这四个实验室使用以下方案：BC-CGID（血清 A1AT 浓度/基因分型/等电聚焦（IEF）/SERPINA1 DNA 测序）、AB-CID（血清 A1AT 浓度/IEF/DNA 测序）、ON-CD（血清 A1AT 浓度/DNA 测序）和 QC-G（基因分型）。由于各自的集水区在大小和种族构成上有所不同，因此通过比较各个基因型与所有方案均能明确识别的 ZZ 基因型的频率，来评估 PV 检测的全面性。

结果

共有 5399 名索引患者接受了检测，确定了 396 个 ZZ 基因型。血清 A1AT 浓度作为进一步检测的决定因素，有效地确定了 PV。ON-CD 具有最高的 PV 检测率；与所有其他基因型（ZZ 基因型除外）相比，除 S、Z 或 F 以外的至少一种 PV 基因型的识别率为 0.67/ZZ，而其他基因型的识别率则<0.2/ZZ。然而，与其他所有方案相比，ON-CD 具有最高的未定义分子变异（UMV）（0.16/ZZ）或可能良性变异（LBV）（0.08/ZZ）的发生率。F 变异仅在 ON-CD 和 AB-CID 方案中以 0.10/ZZ 的频率被识别。总体而言，M 是下一个最常见的变异，仅在 ON-CD 和 BC-CGID 方案中以 0.04/ZZ 的复合杂合基因型被识别。