SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1-INH-HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein-kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin-protease association and a residual 105-kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1-INH-HAE probands presented with an additional so-called intermediate C1-INH-HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype-phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy.