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Inherited Chronic Obstructive Pulmonary Disease: New Selective-Sequencing Workup for ₁-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles

Department of Clinical Chemistry, Meander Medical Center, Amersfoort, The Netherlands.

^aAddress correspondence to this author at: Department of Clinical Chemistry, Meander Medical Center, Utrechtseweg 160, P.O. Box 1502, 3800 BM Amersfoort, The Netherlands. Fax 00-31-78-6523156; e-mail janke.prins{at}hetnet.nl.

Background: ₁-Antitrypsin (₁AT) deficiency predisposes individuals to chronic obstructive pulmonary disease (COPD) and/or liver disease. Phenotyping of the protein by isoelectric focusing is often used to characterize ₁AT deficiency, but this method may lead to misdiagnosis (e.g., by missing null alleles). We evaluated a workup that included direct sequencing of the relevant parts of the gene encoding ₁AT, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1], for patients with ₁AT concentrations 1.0 g/L.

Methods: During a 5-year period, we identified 66 patients with ₁AT concentrations 1.0 g/L and amplified and sequenced exons 2, 3, and 5 of the ₁AT gene in these patients. To ensure that no relevant genotypes were missed, we sequenced the same exons in 48 individuals with ₁AT concentrations between 1.0 and 1.5 g/L.

Results: Sequence analysis revealed 18 patients with combinations of disease-associated ₁AT alleles: 8 homozygous for the deficient Z allele and 10 compound heterozygotes for various deficient or null alleles. We identified and named 2 new null alleles, Q0_soest (Thr¹⁰²delA, which produces a TGA stop signal at codon 112) and Q0_amersfoort (Tyr¹⁶⁰stop). No relevant disease-associated allele combinations were missed at a 1.0-g/L threshold.

Conclusions: Up to 22% of the alleles in disease-associated ₁AT allele combinations may be missed by conventional methods. Genotyping by direct sequencing of samples from patients with ₁AT concentrations 1.0 g/L detected these alleles and identified 2 new null alleles.

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