Description of 22 new alpha-1 antitrypsin genetic variants

Abstract

Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder caused by mutations of the highly polymorphic SERPINA1 gene. This genetic disorder still remains largely under-recognized and can be associated with lung and/or liver injury. The laboratory testing for this deficiency typically comprises serum alpha-1 antitrypsin quantification, phenotyping according to the isoelectric focusing pattern and genotyping if necessary. To date, more than 100 SERPINA1 variants have been described and new genetic variants are frequently discovered. Over the past 10 years, 22 new genetic variants of the SERPINA1 gene were identified in the daily practice of the University Medical laboratories of Lille and Lyon (France). Among these 22 variants, seven were Null alleles and one with a M1 migration pattern (M1Cremeaux) was considered as deficient according to the clinical and biological data and to the American College of Medical Genetics and Genomics (ACMG) criteria. Three other variants were classified as likely pathogenic, three as variants of uncertain significance while the remaining ones were assumed to be neutral. Moreover, we also identified in this study two recently described SERPINA1 deficient variants: Trento (p.Glu99Val) and SDonosti (p.Ser38Phe). The current data, together with a recent published meta-analysis, represent the most up-to-date list of SERPINA1 variants available so far.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0897-0) contains supplementary material, which is available to authorized users.

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.…”

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

“…In overview, SERPINA1 variants exceed the 500, in which more than a third likely have implications for AATD according to clinical data and/or computational predictive tools. 2,12,89 Still and as mentioned above, there are some variants fitting the concept of homoplasy, 2,100 for which the existence of haplotype data is fundamental to address their underlying molecular mechanism. The M Malton and M Palermo (p.Phe52del in M2 and M1Val, respectively) alleles occurring in a short repeat sequence (Table 1) mutational recurrence.…”

“… Notes: a The list of known alleles was retrieved from AATD specialized literature. 3 , 13 , 70–72 , 82–85 , 89 , 90 , 92 , 94 , 99 , 104–111 Molecular background is provided to discriminate alleles carrying the same mutation. b Nucleotide substitutions are underlined, deleted bases are presented in lower case and inserted bases are preceded by an ^ symbol.…”

“… 39 , 88 There are recent reports of additional dysfunctional variants but their rarity has prevented so far, a detailed evaluation of their association with AATD disease. 89 …”

“…Continued). The list of known alleles was retrieved from AATD specialized literature 3,13,[70][71][72][82][83][84][85]89,90,92,94,99,[104][105][106][107][108][109][110][111]. Molecular background is provided to discriminate alleles carrying the same mutation.…”