Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations

Abstract

Rationale Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. Objectives To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. Methods Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. Results A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. Conclusions Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. Clinical Trial Registration This study was registered with clinicaltrials.gov (NCT NCT02810327).

Characteristics of Patients With Alpha-1 Antitrypsin Deficiency From Rural Appalachia: A Retrospective Single-Center Study

“…The normal allele is referred to as "M." The critical variant is the "Z" allele that causes AAT deficiency by homozygous substitution of glutamic acid by lysine at position 342 (Glu342Lys) [ 3 ]. AAT is a protease inhibitor, denoted as "PI" [ 4 ]. The alleles are denoted with related letters.…”

Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

“…As such, many PI*MZ individuals with lower AAT levels and COPD may, in fact, be compound heterozygotes for the Z allele and a rare/M-like allele [ 59 ]. A recent study has reported a high rate of rare deficiency alleles in individuals who were previously identified as PI*MZ [ 60 ], which raises the question of what proportion of PI*MZ patients with severe disease/fast decline are ‘true’ PI*MZs. The challenges to accurately diagnosing rare/M-like Z compound heterozygotes include a lack of awareness and ability to detect rare alleles (e.g., with gene sequencing).…”

The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS

“…These findings need to be evaluated in larger cohorts with sequencing but justifies the sequencing of SERPINA1 in a subgroup of at-risk smokers with COPD, emphysema, and low alpha-1 antitrypsin concentrations in the absence of two pathogenic SNPs covered by chip genotyping panels. Commercial testing kits already perform resequencing in those with alpha-1 antitrypsin deficiency if SERPINA1 panel genotyping is negative (45). A similar, step-wise approach for CFTR resequencing is standard for individuals with clinical features of cystic fibrosis and elevated sweat chloride concentrations despite negative CFTR panel genotyping (46).…”