Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful...
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Autor*in:	Michelle M. Monasky [verfasserIn] Emanuele Micaglio [verfasserIn] Giuseppe Ciconte [verfasserIn] Ilaria Rivolta [verfasserIn] Valeria Borrelli [verfasserIn] Andrea Ghiroldi [verfasserIn] Sara D’Imperio [verfasserIn] Anna Binda [verfasserIn] Dario Melgari [verfasserIn] Sara Benedetti [verfasserIn] Predrag Mitrovic [verfasserIn] Luigi Anastasia [verfasserIn] Valerio Mecarocci [verfasserIn] Žarko Ćalović [verfasserIn] Giorgio Casari [verfasserIn] Carlo Pappone [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	Brugada syndrome sudden cardiac death genetic testing risk stratification variant

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 22(2021), 9, p 4700
Übergeordnetes Werk:	volume:22 ; year:2021 ; number:9, p 4700

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms22094700

Katalog-ID:	DOAJ051710188

Internformat


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allfields	10.3390/ijms22094700 doi (DE-627)DOAJ051710188 (DE-599)DOAJ3f8eba33a24d462fa55d0aead194fe04 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Michelle M. Monasky verfasserin aut Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry Emanuele Micaglio verfasserin aut Giuseppe Ciconte verfasserin aut Ilaria Rivolta verfasserin aut Valeria Borrelli verfasserin aut Andrea Ghiroldi verfasserin aut Sara D’Imperio verfasserin aut Anna Binda verfasserin aut Dario Melgari verfasserin aut Sara Benedetti verfasserin aut Predrag Mitrovic verfasserin aut Luigi Anastasia verfasserin aut Valerio Mecarocci verfasserin aut Žarko Ćalović verfasserin aut Giorgio Casari verfasserin aut Carlo Pappone verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 9, p 4700 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:9, p 4700 https://doi.org/10.3390/ijms22094700 kostenfrei https://doaj.org/article/3f8eba33a24d462fa55d0aead194fe04 kostenfrei https://www.mdpi.com/1422-0067/22/9/4700 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 9, p 4700
spelling	10.3390/ijms22094700 doi (DE-627)DOAJ051710188 (DE-599)DOAJ3f8eba33a24d462fa55d0aead194fe04 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Michelle M. Monasky verfasserin aut Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry Emanuele Micaglio verfasserin aut Giuseppe Ciconte verfasserin aut Ilaria Rivolta verfasserin aut Valeria Borrelli verfasserin aut Andrea Ghiroldi verfasserin aut Sara D’Imperio verfasserin aut Anna Binda verfasserin aut Dario Melgari verfasserin aut Sara Benedetti verfasserin aut Predrag Mitrovic verfasserin aut Luigi Anastasia verfasserin aut Valerio Mecarocci verfasserin aut Žarko Ćalović verfasserin aut Giorgio Casari verfasserin aut Carlo Pappone verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 9, p 4700 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:9, p 4700 https://doi.org/10.3390/ijms22094700 kostenfrei https://doaj.org/article/3f8eba33a24d462fa55d0aead194fe04 kostenfrei https://www.mdpi.com/1422-0067/22/9/4700 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 9, p 4700
allfields_unstemmed	10.3390/ijms22094700 doi (DE-627)DOAJ051710188 (DE-599)DOAJ3f8eba33a24d462fa55d0aead194fe04 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Michelle M. Monasky verfasserin aut Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry Emanuele Micaglio verfasserin aut Giuseppe Ciconte verfasserin aut Ilaria Rivolta verfasserin aut Valeria Borrelli verfasserin aut Andrea Ghiroldi verfasserin aut Sara D’Imperio verfasserin aut Anna Binda verfasserin aut Dario Melgari verfasserin aut Sara Benedetti verfasserin aut Predrag Mitrovic verfasserin aut Luigi Anastasia verfasserin aut Valerio Mecarocci verfasserin aut Žarko Ćalović verfasserin aut Giorgio Casari verfasserin aut Carlo Pappone verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 9, p 4700 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:9, p 4700 https://doi.org/10.3390/ijms22094700 kostenfrei https://doaj.org/article/3f8eba33a24d462fa55d0aead194fe04 kostenfrei https://www.mdpi.com/1422-0067/22/9/4700 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 9, p 4700
allfieldsGer	10.3390/ijms22094700 doi (DE-627)DOAJ051710188 (DE-599)DOAJ3f8eba33a24d462fa55d0aead194fe04 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Michelle M. Monasky verfasserin aut Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry Emanuele Micaglio verfasserin aut Giuseppe Ciconte verfasserin aut Ilaria Rivolta verfasserin aut Valeria Borrelli verfasserin aut Andrea Ghiroldi verfasserin aut Sara D’Imperio verfasserin aut Anna Binda verfasserin aut Dario Melgari verfasserin aut Sara Benedetti verfasserin aut Predrag Mitrovic verfasserin aut Luigi Anastasia verfasserin aut Valerio Mecarocci verfasserin aut Žarko Ćalović verfasserin aut Giorgio Casari verfasserin aut Carlo Pappone verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 9, p 4700 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:9, p 4700 https://doi.org/10.3390/ijms22094700 kostenfrei https://doaj.org/article/3f8eba33a24d462fa55d0aead194fe04 kostenfrei https://www.mdpi.com/1422-0067/22/9/4700 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 9, p 4700
allfieldsSound	10.3390/ijms22094700 doi (DE-627)DOAJ051710188 (DE-599)DOAJ3f8eba33a24d462fa55d0aead194fe04 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Michelle M. Monasky verfasserin aut Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry Emanuele Micaglio verfasserin aut Giuseppe Ciconte verfasserin aut Ilaria Rivolta verfasserin aut Valeria Borrelli verfasserin aut Andrea Ghiroldi verfasserin aut Sara D’Imperio verfasserin aut Anna Binda verfasserin aut Dario Melgari verfasserin aut Sara Benedetti verfasserin aut Predrag Mitrovic verfasserin aut Luigi Anastasia verfasserin aut Valerio Mecarocci verfasserin aut Žarko Ćalović verfasserin aut Giorgio Casari verfasserin aut Carlo Pappone verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 9, p 4700 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:9, p 4700 https://doi.org/10.3390/ijms22094700 kostenfrei https://doaj.org/article/3f8eba33a24d462fa55d0aead194fe04 kostenfrei https://www.mdpi.com/1422-0067/22/9/4700 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 9, p 4700
language	English
source	In International Journal of Molecular Sciences 22(2021), 9, p 4700 volume:22 year:2021 number:9, p 4700
sourceStr	In International Journal of Molecular Sciences 22(2021), 9, p 4700 volume:22 year:2021 number:9, p 4700
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Michelle M. Monasky @@aut@@ Emanuele Micaglio @@aut@@ Giuseppe Ciconte @@aut@@ Ilaria Rivolta @@aut@@ Valeria Borrelli @@aut@@ Andrea Ghiroldi @@aut@@ Sara D’Imperio @@aut@@ Anna Binda @@aut@@ Dario Melgari @@aut@@ Sara Benedetti @@aut@@ Predrag Mitrovic @@aut@@ Luigi Anastasia @@aut@@ Valerio Mecarocci @@aut@@ Žarko Ćalović @@aut@@ Giorgio Casari @@aut@@ Carlo Pappone @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ051710188
language_de	englisch
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callnumber-first	Q - Science
author	Michelle M. Monasky
spellingShingle	Michelle M. Monasky misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc genetic testing misc <i<SCN5A</i< misc risk stratification misc variant misc Biology (General) misc Chemistry Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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topic_title	QH301-705.5 QD1-999 Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths Brugada syndrome sudden cardiac death genetic testing <i<SCN5A</i< risk stratification variant
topic	misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc genetic testing misc <i<SCN5A</i< misc risk stratification misc variant misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc genetic testing misc <i<SCN5A</i< misc risk stratification misc variant misc Biology (General) misc Chemistry
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title	Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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title_full	Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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author_browse	Michelle M. Monasky Emanuele Micaglio Giuseppe Ciconte Ilaria Rivolta Valeria Borrelli Andrea Ghiroldi Sara D’Imperio Anna Binda Dario Melgari Sara Benedetti Predrag Mitrovic Luigi Anastasia Valerio Mecarocci Žarko Ćalović Giorgio Casari Carlo Pappone
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author-letter	Michelle M. Monasky
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title_sort	novel <i<scn5a</i< p.val1667asp missense variant segregation and characterization in a family with severe brugada syndrome and multiple sudden deaths
callnumber	QH301-705.5
title_auth	Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
abstract	Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.
abstractGer	Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.
abstract_unstemmed	Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the <i<SCN5A</i< gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the <i<SCN5A</i< novel variant <i<in vitro</i<. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T<A (p.Val1667Asp) in the <i<SCN5A</i< gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.
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title_short	Novel <i<SCN5A</i< p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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