BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. OBJECTIVE: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. METHODS: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1-INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. RESULTS: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1-INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1-INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. CONCLUSION: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1-INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1-INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1-INH level.
- Publikační typ
- časopisecké články MeSH
Bežná variabilná imunodeficiencia je heterogénnou skupinou ochorení, ktoré spája podobný laboratórny nález v imunoprofile. Hoci ide o prevažne protilátkovú poruchu imunity, zmeny a odchýlky nachádzame aj v oblasti celulárnej imunity. Diagnostické kritériá a klasifikačné systémy zatiaľ nie sú schopné stanoviť klinicky plne využiteľné fenotypové rozdelenie pacientov. V tejto problematike by mohla kľúčovú úlohu zohrať genotypová klasifikácia. Zoznam kauzálnych génov pre vznik ochorenia sa neustále rozširuje. Mutácie v známych génoch sa ale potvrdia len u približne 10–25 % pacientov. Aj tieto nálezy je potrebné správne interpretovať, čo je často značne komplikované. Medzi ďalšie zvažované príčinné faktory vzniku patria epigenetické zmeny, oligogénna a polygénna dedičnosť alebo vplyv vonkajšieho prostredia.
Common variable immunodeficiency is heterogeneous group of disorders that belongs to primary immunodeficiency disorders. Combined defect of humoral and cellular immunity is the main sign. Diagnostic criteria and classification are still insufficient for optimal clinical use. This problem can be solved by genotype classification. There are many causal genes but these are found only in 10 % to 25 % of the patients. Moreover, these findings have to be interpreted correctly, which is complicated. Other possible causes are epigenetics, oligogenic, polygenic inheritance and environmental factors.
- Publikační typ
- abstrakt z konference MeSH
