Abstract Introduction Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition caused by a variety of gene variants of the SERPINA1 gene on chromosome 14 (14q32.1), resulting in insufficient circulating levels of alpha-1 antitrypsin (AAT). The degree of AAT protein deficiency confers varying risks of emphysema and liver disease. Null alleles are a subgroup of rare SERPINA1 variants, which cause a complete absence of AAT protein production and confer the highest risk of pulmonary damage. Interestingly, in the absence of polymerisation of misfolded proteins, there is no toxic accumulation within hepatocytes, negating the risk of liver disease. We will describe the Irish cohort of patients with six different Null variants and compare their clinical phenotypes to their more prevalent AATD counterparts, MZ and ZZ. Methods Patients with Null variants were identified via the National Targeted Detection Programme database. Individuals attending the National Centre of Expertise for AATD for clinical assessment were included in this study. Results We present 10 patients with AATD caused by Null alleles, including frameshift variants; Q0dublin and Q0bolton, and the intronic variant; Q0porto. We have further subcategorized this group, based on the nature of their accompanying allele, allowing a functional comparison of M/Null, Z/Null and a single case of Null/Null. We have gathered longitudinal data from these ten patients, including spirometry, CT thorax and hepatic assessment using Fibroscan and liver function tests. Emphysema is present in every individual with Z/Null and Null/Null phenotypes (n = 5), despite smoking status. The average age of symptom onset is 38 (+/- 8 years). Conversely, hepatic fibrosis is notably absent. This reflects the underlying pathophysiology of null variants, which confer an increased risk of lung disease and decreased risk of liver disease, in comparison to the more common ZZ phenotype. Conclusions Null SERPINA1 alleles are under-diagnosed. They do not generate a band on isoelectric focusing and may be missed on allele-specific genotype analysis, with results often incorrectly interpreted as homozygous for the other allele. The exciting therapeutics currently in trial, chiefly base-editing gene therapies, target the considerably more common Z variant, and as such will not be beneficial to individuals with Null variants. Accurate genetic diagnosis will be paramount to appropriate patient selection for treatment and depends on increased awareness, use of multiple collaborative diagnostic techniques and expert interpretation. This abstract is funded by: .
Farrell et al. (Fri,) studied this question.