SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE

<jats:p>Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the<jats:italic>SERPING1</jats:italic>gene (<jats:italic>n</jats:italic>= 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of<jats:italic>SERPING1</jats:italic>and pertaining to 5.6%<jats:italic>de novo</jats:italic>variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE.<jats:italic>SERPING1</jats:italic>variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (<jats:italic>n</jats:italic>= 25). Exonic variants (<jats:italic>n</jats:italic>= 6) can affect exon splicing. Rare deep-intron variants (<jats:italic>n</jats:italic>= 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (<jats:italic>n</jats:italic>= 74). This category includes some homozygous (<jats:italic>n</jats:italic>= 10) or compound heterozygous variants (<jats:italic>n</jats:italic>= 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a<jats:italic>de novo</jats:italic>variant. Situations with paternal or maternal disomy have been recorded (<jats:italic>n</jats:italic>= 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any<jats:italic>SERPING1</jats:italic>variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.</jats:p>