Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in the SERPING1 gene. Homozygosity for SERPING1 pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. In this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed to SERPING1 variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients.