Researchers from Quebec, Canada, reported a case of alpha-1 antitrypsin deficiency (AATD) caused by a null variant inherited through a so-called copy-neutral loss of heterozygosity event. This is the first case of AATD caused by such a genetic event and is important because it highlights a new genetic mechanism causing AATD.

As they were conducting a clinical screening for AATD, a team of researchers led by Yohan Bossé, PhD, from the Quebec Heart and Lung Institute at Laval University in Quebec City encountered the unusual case of a woman with severe asthma that rapidly evolved into a fixed airway obstruction at age 33. In spite of optimal asthma treatment, her lung function continued to decline. Based on clinical and imaging findings, the researchers reported that she likely had AATD

They then investigated the patient in terms of serum AAT levels and SERPINA1 DNA sequence. Based on these tests, they reported that her serum concentration of AAT was undetectable by immunoturbidimetry and ELISA, and that she had a rare null mutation caused by the insertion of a single “T” nucleotide, which led to a frameshift and a premature stop codon.

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The patient was homozygous for this mutation, as she was for other variants of the SERPINA1 gene.

Read more about the etiology of AATD.

Using a single nucleotide polymorphism array that focused on chromosome 14 where the SERPINA1 gene is located, the researchers showed that the patient had a copy-neutral loss of heterozygosity event spanning the segment of DNA carrying the AATD-causing mutation. 

When they studied the family history of the patient, the researchers discovered she was the daughter of second cousins and found 25 additional loss of heterozygosity events genomewide, the sum of the lengths of which was 92.4 Mb, “which is consistent with the range expected in the offspring of second cousins,” the authors said. 


Gaudreault N, Blouin C, Haillot A, Milot J, Maltais F, Bossé Y. The null Q0Ourém variant within a copy-neutral loss-of-heterozygosity event causing alpha-1 antitrypsin deficiency. Am J Respir Cell Mol Biol. 2022;66(6):700-702. doi:10.1165/rcmb.2021-0564LE