Background and Objectives: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare autosomal dominant disorder caused by mutations in the SERPING1 gene and is characterized by considerable clinical variability among affected individuals. Although genotype–phenotype correlations have been reported, data from populations with high consanguinity rates remain limited. Therefore, this study aimed to construct pedigrees of HAE-C1INH families harboring SERPING1 mutations and to investigate whether mutation type is associated with phenotypic characteristics, particularly age at disease onset and C1 inhibitor functional activity. Materials and Methods: Eleven HAE-C1INH probands and their families were followed up at the Allergy and Immunology Department of Internal Medicine, Ege University Faculty of Medicine. Of the 295 family members identified through pedigree construction, 109 had symptoms compatible with HAE-C1INH, and 53 of these symptomatic individuals had both a confirmed SERPING1 genetic result and an available C1-INH functional measurement. Pedigrees were created using the Progeny Pedigree Drawing Software (Progeny Genetics LLC, Delray Beach, FL, USA). Demographic data, disease characteristics, C1-INH function levels, and SERPING1 mutation types were obtained from patient files. Results: A total of 295 individuals (151 males and 144 females) from 11 HAE-C1INH families were identified through pedigree construction. The analytical cohort comprised 53 symptomatic individuals, of whom 7 (13.2%) were homozygous for the variant. Among heterozygous patients (n = 46), 27 (58.7%) had missense mutations, 7 (15.2%) had nonsense mutations, 7 (15.2%) had large deletions, and 5 (10.9%) had frameshift deletion mutations. Patients carrying missense mutations had significantly higher median C1-INH functional activity (28.5%) than those with other mutation types (14.1%) (p = 0.026), and the median age of disease onset was significantly later in the missense group (20 years) than in the non-missense group (8 years) (p < 0.001). Annual HAE attack frequency was also lower in the missense group (median, 12 vs. 48 attacks per year; p = 0.009). Conclusions: Exploratory individual-level analyses showed higher residual C1-INH functional activity and later symptom onset among individuals carrying missense SERPING1 variants than among those carrying pooled non-missense loss-of-function variants. However, familial clustering and the small number of independent families limit the strength and generalizability of these findings.

Purpose: In this eight-year study, children with unclassified inborn errors of immunity (IEI) who have no pathogenic variants in targeted next-generation sequencing (tNGS) were re-evaluated by using singleton whole exome sequencing (sWES) and followed-up at least five years. They were also investigated if they had affected family members or not. In addition, all patients had detailed immunological and clinical work-up. Methods: In 2017, 108 children with probable diagnosis of IEI had tNGS and pathogenic variants were detected in 38 (35.1%) patients who were not included into the study. The rest 70 patients were continued to be immunologicaly followed-up (67.0 ± 19.7 months) and 15 of them (21.4%) recovered spontaneously. Fifty-five patients were divided into two groups; (i) familial patients (n = 30); (ii) non-familial patients (n = 25). In all of them, sWES analysis was performed. Results: There were 19 affected fathers, 9 mothers and 16 siblings whereas consanguinity rate for parents was 8.5%. In sWES analysis, no genetic alterations were detected in 28 (50.9%) patients and 14 cases showed predefined pathogenic variants which are not associated with IEI. Probable IEI causing variants were found in 13 of 55 cases. However, after genotype/phenotype examinations and segregation analysis by sanger sequencing for their parents, we were able to define only three pathogenic variants in three cases, namely two for IKBKB gene and one for PRKDC in familial cases. Fifty-five cases were screened with sWES and only three pathogenic variants were revealed (3/55, 5.45%). When we add this result to tNGS finding (35.1%), all together 40.55% of unclassifed IEI cases could be defined by both of these genetic investigations. Conclusion: Even with NGS-based approaches improving IEI diagnoses, detection rates still remain below 50%. Whole genome sequencing in the near future would offer the advantage of much more comprehensive and accurate variant detections.