Systematic Approach Revealed SERPING1 Splicing-Affecting
Variants to be Highly Represented in the Czech National HAE
Cohort

J 2023

Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort

GROMBIŘÍKOVÁ, Hana, Viktor BÍLY, Přemysl SOUČEK, Michal KRAMÁREK, Roman HAKL et. al.

Basic information

Original name

Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort

Authors

GROMBIŘÍKOVÁ, Hana (203 Czech Republic, belonging to the institution), Viktor BÍLY (703 Slovakia, belonging to the institution), Přemysl SOUČEK (203 Czech Republic, belonging to the institution), Michal KRAMÁREK (703 Slovakia, belonging to the institution), Roman HAKL (203 Czech Republic, belonging to the institution), Lucie BALLONOVÁ (203 Czech Republic, belonging to the institution), Barbora RAVCUKOVA, Dita RICNA, Karolína KOŽENÁ (203 Czech Republic, belonging to the institution), Lucie KRATOCHVÍLOVÁ (203 Czech Republic), Marta SOBOTKOVA (203 Czech Republic), Radana ZACHOVA (203 Czech Republic), Pavel KUKLÍNEK (203 Czech Republic, belonging to the institution), Pavlina KRALICKOVA (203 Czech Republic), Irena KRCMOVA (203 Czech Republic), Jana HANZLIKOVA (203 Czech Republic), Martina VACHOVA (203 Czech Republic), Olga KRYSTUFKOVA (203 Czech Republic), Eva DANKOVA (203 Czech Republic), Milos JESENAK (703 Slovakia), Martina NOVACKOVA (203 Czech Republic), Michal SVOBODA (203 Czech Republic), Jiří LITZMAN (203 Czech Republic, belonging to the institution) and Tomáš FREIBERGER (203 Czech Republic, belonging to the institution)

Edition

Journal of Clinical Immunology, NEW YORK, SPRINGER, 2023, 0271-9142

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30102 Immunology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 9.100 in 2022

RIV identification code

RIV/00216224:14110/23:00132410

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1007/s10875-023-01565-w

UT WoS

001063524100001

Keywords in English

HAE; C1-INH-HAE; hereditary angioedema; SERPING1; splicing genotype–phenotype relationship; time to diagnosis

Abstract

V originále

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype–phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.

Links

MUNI/A/1098/2022, interní kód MU

Name: Nespecifická imunita u chorob imunitního systému

Investor: Masaryk University, Non-specific immunity in immune system diseases

NV18-05-00330, research and development project

Name: Genetická determinace závažnosti otoků podmíněných bradykininem u pacientů s hereditárním angioedémem

Investor: Ministry of Health of the CR, Genetic determination of bradykinin-mediated angioedema severity in patients with hereditary angioedema

Citovat

GROMBIŘÍKOVÁ, Hana, Viktor BÍLY, Přemysl SOUČEK, Michal KRAMÁREK, Roman HAKL, Lucie BALLONOVÁ, Barbora RAVCUKOVA, Dita RICNA, Karolína KOŽENÁ, Lucie KRATOCHVÍLOVÁ, Marta SOBOTKOVA, Radana ZACHOVA, Pavel KUKLÍNEK, Pavlina KRALICKOVA, Irena KRCMOVA, Jana HANZLIKOVA, Martina VACHOVA, Olga KRYSTUFKOVA, Eva DANKOVA, Milos JESENAK, Martina NOVACKOVA, Michal SVOBODA, Jiří LITZMAN and Tomáš FREIBERGER. Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort. Journal of Clinical Immunology. NEW YORK: SPRINGER, 2023, vol. 43, No 8, p. 1974-1991. ISSN 0271-9142. Available from: https://dx.doi.org/10.1007/s10875-023-01565-w.

@article{2345961,
   author = {Grombiříková, Hana and Bíly, Viktor and Souček, Přemysl and Kramárek, Michal and Hakl, Roman and Ballonová, Lucie and Ravcukova, Barbora and Ricna, Dita and Kožená, Karolína and Kratochvílová, Lucie and Sobotkova, Marta and Zachova, Radana and Kuklínek, Pavel and Kralickova, Pavlina and Krcmova, Irena and Hanzlikova, Jana and Vachova, Martina and Krystufkova, Olga and Dankova, Eva and Jesenak, Milos and Novackova, Martina and Svoboda, Michal and Litzman, Jiří and Freiberger, Tomáš},
   article_location = {NEW YORK},
   article_number = {8},
   doi = {http://dx.doi.org/10.1007/s10875-023-01565-w},
   keywords = {HAE; C1-INH-HAE; hereditary angioedema; SERPING1; splicing genotype–phenotype relationship; time to diagnosis},
   language = {eng},
   issn = {0271-9142},
   journal = {Journal of Clinical Immunology},
   title = {Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort},
   url = {https://link.springer.com/article/10.1007/s10875-023-01565-w},
   volume = {43},
   year = {2023}
}

TY  - JOUR
ID  - 2345961
AU  - Grombiříková, Hana - Bíly, Viktor - Souček, Přemysl - Kramárek, Michal - Hakl, Roman - Ballonová, Lucie - Ravcukova, Barbora - Ricna, Dita - Kožená, Karolína - Kratochvílová, Lucie - Sobotkova, Marta - Zachova, Radana - Kuklínek, Pavel - Kralickova, Pavlina - Krcmova, Irena - Hanzlikova, Jana - Vachova, Martina - Krystufkova, Olga - Dankova, Eva - Jesenak, Milos - Novackova, Martina - Svoboda, Michal - Litzman, Jiří - Freiberger, Tomáš
PY  - 2023
TI  - Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort
JF  - Journal of Clinical Immunology
VL  - 43
IS  - 8
SP  - 1974-1991
EP  - 1974-1991
PB  - SPRINGER
SN  - 02719142
KW  - HAE
KW  - C1-INH-HAE
KW  - hereditary angioedema
KW  - SERPING1
KW  - splicing genotype–phenotype relationship
KW  - time to diagnosis
UR  - https://link.springer.com/article/10.1007/s10875-023-01565-w
N2  - Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype–phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.
ER  -

GROMBIŘÍKOVÁ, Hana, Viktor BÍLY, Přemysl SOUČEK, Michal KRAMÁREK, Roman HAKL, Lucie BALLONOVÁ, Barbora RAVCUKOVA, Dita RICNA, Karolína KOŽENÁ, Lucie KRATOCHVÍLOVÁ, Marta SOBOTKOVA, Radana ZACHOVA, Pavel KUKLÍNEK, Pavlina KRALICKOVA, Irena KRCMOVA, Jana HANZLIKOVA, Martina VACHOVA, Olga KRYSTUFKOVA, Eva DANKOVA, Milos JESENAK, Martina NOVACKOVA, Michal SVOBODA, Jiří LITZMAN and Tomáš FREIBERGER. Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort. \textit{Journal of Clinical Immunology}. NEW YORK: SPRINGER, 2023, vol.~43, No~8, p.~1974-1991. ISSN~0271-9142. Available from: https://dx.doi.org/10.1007/s10875-023-01565-w.

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