Undetected mutations across different serum alpha1 antitrypsin thresholds: An analysis of the avatar cohort

The optimal serum alpha-1 antitrypsin (AAT) cut-off for prompting genotyping in alpha-1 antitrypsin deficiency (AATD) remains debated, with limited data on mutations missed at different thresholds. This study assessed the frequency and spectrum of mutations potentially overlooked when applying varying serum AAT values.

Data were analysed from the Andalusian Valuable and Transdisciplinary AATD Registry (AVATAR), a prospective cohort undergoing standardised AATD evaluation. Serum AAT and C-reactive protein were measured, followed by SERPINA1 genotyping. Mutation detection rates were examined at thresholds of 90, 100, 110, 116, and 120 mg/dL.

Among 492 participants (mean age 53.8 years; 53.0% male), 320 (65.0%) carried at least one mutation, most frequently PIMS (29.7%) and PIMZ (18.1%). At 90 mg/dL, 188 individuals (52.5%) above this value still harboured mutations, including 36 (10.0%) with potentially severe genotypes. Raising the threshold progressively reduced missed mutations, but no PIZZ or PISZ cases were found above any cut-off.

Serum AAT threshold selection substantially affects mutation detection. Lower thresholds prioritise severe genotypes, while higher thresholds capture more carriers, facilitating cascade screening but increasing workload. Thresholds should be tailored to the clinical and public health aims of screening.