Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

Abstract

The growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. "Benign" and "pathogenic" variations were used to assess performance of 31 pathogenicity predictors. Well-performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterization in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behavior of the pathogenic new variants and consistent outliers were rationalized by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation.

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

“…Since organoids are derived directly from the affected individuals, they may also help us to elucidate the complex heterogeneity of liver disease among AATD carriers. In addition to Z-AAT mutation, many other rare alleles associated with AAT deficiency have been described [19,28,29] for which the potential damaging effects in hepatocytes are unknown. Organoids derived from patients carrying other than the Z variant would help to investigate the mechanisms of accumulation, secretion and degradation of these much less studied AAT variants.…”

Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population

“…The ExAC consortium [26] is a free-to-access repository presently containing about 60,706 exome sequences, gathered from several human populations. By querying this database, it is possible to identify novel putatively pathogenic variants of proteins including AAT [27]. From this and other human population databases, we have evaluated novel SERPINA1 variants that fall within the RCL domain—a region critical to the inhibitory mechanism—with the aim of identifying novel dysfunctional variants in the general population.…”

Modernising case finding for α1-antitrypsin deficiency by DNA sequencing of COPD patients

“…A potential area for improvement within the manuscript is the choice of method to group the genotypes, which was based mainly on the predicted effects on pathogenicity. Whilst the authors concede their approach is imperfect it might have strengthened the work if an already established approach for pathogenicity prediction had been used [17]. Furthermore, as CanCOLD is a study of the general population, a demographic breakdown of the subjects could have been useful to assess any associations between deficient alleles and ethnicity, considering Canada's sizeable indigenous population [18].…”