AUTHOR=Drouet Christian , López-Lera Alberto , Ghannam Arije , López-Trascasa Margarita , Cichon Sven , Ponard Denise , Parsopoulou Faidra , Grombirikova Hana , Freiberger Tomáš , Rijavec Matija , Veronez Camila L. , Pesquero João Bosco , Germenis Anastasios E. 

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

JOURNAL=Frontiers in Allergy

VOLUME=Volume 3 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/allergy/articles/10.3389/falgy.2022.835503

DOI=10.3389/falgy.2022.835503

ISSN=2673-6101

ABSTRACT=Hereditary angioedema with C1-INH deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n=809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein-kinin system (KKS). Besides C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing failed control of C1s protease or KKS provides diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with incomplete penetrance and low prevalence. A great majority of variants (809/893; 90.5%) that were introduced in 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 not uncommon, with exon 4 as the most affected. 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, as well (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients’ blood-derived RNAs (n=25). Exonic variants (n=6) can affect exon splicing. Rare deep-intron variants (n=6), putatively acting as pseudoexon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n=74). This category includes some homozygous (n=10) or compound heterozygous variants (n=11). They are presenting with 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 de novo variant. Situations with both paternal or maternal disomy have been recorded (n=3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.