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2018 | 23 | 4 | 205-210
Article title

Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene

Title variants
Wybrane aspekty genotypowania wrodzonego obrzęku naczynioruchowego w erze NGS: gen F12
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Objective. To screen a cohort of patients diagnosed with non-FXII angioedema for carriage of variants of F12 gene. Material and methods. DNA samples from 191 patients suffering from primary angioedema with normal C1-INH, 54 samples from non- -affected family members, and 161 samples from C1-INH-HAE (154 type I, 7 type II) patients were included in the study. The F12 gene was genotyped by targeted NGS (100% coverage of translated regions). Sanger sequencing was performed for the verification of all identified variants and family segregation studies. Results. The pathogenic F12 variant c.983C>A was detected in three patients from two unrelated families initially diagnosed as U-HAE. Six additional mutations were identified, four of which were characterized as benign (c.41T>C, c.418C>G, c.1025C>T, c.530C>T) and two of uncertain significance (c.1530G>C, c.1768T>G). Two synonymous variants (c.756C>T and c.711C>T), the common polymorphism c.619G>C, and the functional polymorphism c.-4T>C were detected in allele frequencies similar to those presented in the ExAC database for the European population. One more not yet reported synonymous variant (c. 1599A>G) was also found. Conclusion. Analyzing the entire translated region of F12 gene is important in order to identify new variants that possibly affect HAE expressivity. Interestingly, genetic analysis of F12 supports not only the diagnosis of FXII-HAE but also the correct exclusion diagnosis of U-HAE.
Cel. Przesiewowe badanie kohorty pacjentów z rozpoznanym obrzę- kiem naczynioruchowym innym niż zależny od FXII w kierunku nosicielstwa wariantów genu F12. Materiał i metody. Do badania włączono próbki DNA 191 pacjentów cierpiących na pierwotny obrzęk naczynioruchowy z prawidłowym C1-INH, 54 zdrowych członków rodzin oraz 161 pacjentów z C1-INH-HAE (154 typ I, 7 typ II). Gen F12 był genotypowany metodą NGS (obejmującą cały rejon poddany translacji). Sekwencjonowanie metodą Sangera zostało wykonane celem weryfikacji wszystkich zidentyfikowanych wariantów i badań segregacyjnych rodzin. Wyniki. U trzech pacjentów z dwóch niespokrewnionych rodzin pierwotnie zdiagnozowanych jako U-HAE wykryto patogenny wariant F12: c.983C>A. Zidentyfikowano sześć dodatkowych mutacji, z których cztery zostały określone jako łagodne (c.41T>C, c.418C>G, c.1025C>T, c.530C>T), a dwie jako mutacje o niepewnym znaczeniu (c.1530G>C, c.1768T>G). Stwierdzono dwa warianty synonimiczne (c.756C>T oraz c.711C>T), pospolity polimorfizm (c.619G>C) oraz czynnościowy polimorfizm c.-4T>C z częstością alleliczną podobną do podawanej w bazie ExAC dla populacji europejskiej. Wykryto również jeden nie raportowany dotychczas wariant synonimiczny (c. 1599A>G). Wnioski. Analiza całego rejonu genu F12 poddawanego translacji jest ważna dla identyfikowania nowych wariantów, które mogą oddziaływać na ekspresję HAE. Ponadto, analiza genetyczna F12 pozwala nie tylko na potwierdzenie rozpoznania FXII-HAE, ale również prawidłowe wykluczenie rozpoznania U-HAE.
Physical description
  • CeMIA SA, Larissa, Greece, Department of Immunology & Histocompatibility, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece
  • CeMIA SA, Larissa, Greece
  • CeMIA SA, Larissa, Greece
  • Reference Unit for Angioedema in Andalusia, Allergy Department, Hospital Universitario Virgen del Rocio, Seville, Spain
  • Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland
  • Centre of Pulmonology and Thoracic Surgery, Poznan, Poland
  • Department of Translational Medicine, University Federico II, Naples, Italy
  • Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
  • Hungarian Angioedema Reference Center, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
  • Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece
  • Clinical Centre of Allergology, Medical University, Sofia, Bulgaria
  • Clinical Centre of Allergology, Medical University, Sofia, Bulgaria
  • Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Germany
  • Hungarian Angioedema Reference Center, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
  • CeMIA SA, Larissa, Greece, Department of Immunology & Histocompatibility, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece
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