In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic

Autores
Buonfiglio, Paula Inés; Bruque, Carlos David; Goldschmidt, Ernesto; Lotersztein, Vanesa; Menazzi, Sebastián; Paoli, Bibiana; Plazas, Paola Viviana; Elgoyhen, Ana Belen; Dalamon, Viviana Karina
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Hereditary hearing loss (HHL) is the most common sensory disorder affecting 1 in 500 newborn children. Since HHL is related to more than 150 target genes, we designed a diagnosis strategy in order to identify pathogenic variants.A total of 1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing, genotyping 25% of them. From undiagnosed patients, 29 families were selected to perform Whole exome sequencing. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG Standards.Some of the novel variants were further studied in silico by structural and stability studies of the mutated proteins. In addition, datasets from deafness and specific variant databases were correlated with different protein motifs in order to predict the theoretical pathogenicity effect of the aminoacid changes. Furthermore, knock-down phenotype rescue assays in zebrafish are underway to accomplish in vivo validation. In some cases, extensive analysis reinforced the pathogenicity prediction effect of variants and surprisingly, in one case, discouraged the deleterious effect of a genetic variant to the protein.Preliminary results in zebrafish confirmed the pathogenicity of one novel variant in the hair cell function and auditory system.This study shows that our algorithm is successful for the genetic diagnosis of deafness. Comprehensive analysis is crucial to strengthen prediction of variant pathogenicity. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of HHL.
Fil: Buonfiglio, Paula Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bruque, Carlos David. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina
Fil: Goldschmidt, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina
Fil: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina
Fil: Menazzi, Sebastián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Paoli, Bibiana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; Argentina
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Dalamon, Viviana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
53rd European Society of Human Genetics Conference
Viena
Austria
European Society of Human Genetics
Materia
WES
HEARING LOSS
GENETICS
BIOINFORMATICS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/202568
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/202568
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenicBuonfiglio, Paula InésBruque, Carlos DavidGoldschmidt, ErnestoLotersztein, VanesaMenazzi, SebastiánPaoli, BibianaPlazas, Paola VivianaElgoyhen, Ana BelenDalamon, Viviana KarinaWESHEARING LOSSGENETICSBIOINFORMATICShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Hereditary hearing loss (HHL) is the most common sensory disorder affecting 1 in 500 newborn children. Since HHL is related to more than 150 target genes, we designed a diagnosis strategy in order to identify pathogenic variants.A total of 1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing, genotyping 25% of them. From undiagnosed patients, 29 families were selected to perform Whole exome sequencing. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG Standards.Some of the novel variants were further studied in silico by structural and stability studies of the mutated proteins. In addition, datasets from deafness and specific variant databases were correlated with different protein motifs in order to predict the theoretical pathogenicity effect of the aminoacid changes. Furthermore, knock-down phenotype rescue assays in zebrafish are underway to accomplish in vivo validation. In some cases, extensive analysis reinforced the pathogenicity prediction effect of variants and surprisingly, in one case, discouraged the deleterious effect of a genetic variant to the protein.Preliminary results in zebrafish confirmed the pathogenicity of one novel variant in the hair cell function and auditory system.This study shows that our algorithm is successful for the genetic diagnosis of deafness. Comprehensive analysis is crucial to strengthen prediction of variant pathogenicity. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of HHL.Fil: Buonfiglio, Paula Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bruque, Carlos David. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; ArgentinaFil: Goldschmidt, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Menazzi, Sebastián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Paoli, Bibiana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Dalamon, Viviana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina53rd European Society of Human Genetics ConferenceVienaAustriaEuropean Society of Human GeneticsNature Publishing Group2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectConferenciaJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/202568In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic; 53rd European Society of Human Genetics Conference; Viena; Austria; 2020; 189-1891018-48131476-5438CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41431-020-00739-zinfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41431-020-00739-zInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:57:16Zoai:ri.conicet.gov.ar:11336/202568instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:57:16.792CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
title In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
spellingShingle In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
Buonfiglio, Paula Inés
WES
HEARING LOSS
GENETICS
BIOINFORMATICS
title_short In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
title_full In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
title_fullStr In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
title_full_unstemmed In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
title_sort In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic
dc.creator.none.fl_str_mv Buonfiglio, Paula Inés
Bruque, Carlos David
Goldschmidt, Ernesto
Lotersztein, Vanesa
Menazzi, Sebastián
Paoli, Bibiana
Plazas, Paola Viviana
Elgoyhen, Ana Belen
Dalamon, Viviana Karina
author Buonfiglio, Paula Inés
author_facet Buonfiglio, Paula Inés
Bruque, Carlos David
Goldschmidt, Ernesto
Lotersztein, Vanesa
Menazzi, Sebastián
Paoli, Bibiana
Plazas, Paola Viviana
Elgoyhen, Ana Belen
Dalamon, Viviana Karina
author_role author
author2 Bruque, Carlos David
Goldschmidt, Ernesto
Lotersztein, Vanesa
Menazzi, Sebastián
Paoli, Bibiana
Plazas, Paola Viviana
Elgoyhen, Ana Belen
Dalamon, Viviana Karina
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv WES
HEARING LOSS
GENETICS
BIOINFORMATICS
topic WES
HEARING LOSS
GENETICS
BIOINFORMATICS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Hereditary hearing loss (HHL) is the most common sensory disorder affecting 1 in 500 newborn children. Since HHL is related to more than 150 target genes, we designed a diagnosis strategy in order to identify pathogenic variants.A total of 1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing, genotyping 25% of them. From undiagnosed patients, 29 families were selected to perform Whole exome sequencing. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG Standards.Some of the novel variants were further studied in silico by structural and stability studies of the mutated proteins. In addition, datasets from deafness and specific variant databases were correlated with different protein motifs in order to predict the theoretical pathogenicity effect of the aminoacid changes. Furthermore, knock-down phenotype rescue assays in zebrafish are underway to accomplish in vivo validation. In some cases, extensive analysis reinforced the pathogenicity prediction effect of variants and surprisingly, in one case, discouraged the deleterious effect of a genetic variant to the protein.Preliminary results in zebrafish confirmed the pathogenicity of one novel variant in the hair cell function and auditory system.This study shows that our algorithm is successful for the genetic diagnosis of deafness. Comprehensive analysis is crucial to strengthen prediction of variant pathogenicity. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of HHL.
Fil: Buonfiglio, Paula Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bruque, Carlos David. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina
Fil: Goldschmidt, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina
Fil: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina
Fil: Menazzi, Sebastián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Paoli, Bibiana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; Argentina
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Dalamon, Viviana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
53rd European Society of Human Genetics Conference
Viena
Austria
European Society of Human Genetics
description Hereditary hearing loss (HHL) is the most common sensory disorder affecting 1 in 500 newborn children. Since HHL is related to more than 150 target genes, we designed a diagnosis strategy in order to identify pathogenic variants.A total of 1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing, genotyping 25% of them. From undiagnosed patients, 29 families were selected to perform Whole exome sequencing. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG Standards.Some of the novel variants were further studied in silico by structural and stability studies of the mutated proteins. In addition, datasets from deafness and specific variant databases were correlated with different protein motifs in order to predict the theoretical pathogenicity effect of the aminoacid changes. Furthermore, knock-down phenotype rescue assays in zebrafish are underway to accomplish in vivo validation. In some cases, extensive analysis reinforced the pathogenicity prediction effect of variants and surprisingly, in one case, discouraged the deleterious effect of a genetic variant to the protein.Preliminary results in zebrafish confirmed the pathogenicity of one novel variant in the hair cell function and auditory system.This study shows that our algorithm is successful for the genetic diagnosis of deafness. Comprehensive analysis is crucial to strengthen prediction of variant pathogenicity. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of HHL.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Conferencia
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/202568
In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic; 53rd European Society of Human Genetics Conference; Viena; Austria; 2020; 189-189
1018-4813
1476-5438
CONICET Digital
CONICET
url http://hdl.handle.net/11336/202568
identifier_str_mv In silico and in vivo analyses of novel variants identified by Whole Exome Sequencing in Argentinean deaf patients: To be or not be pathogenic; 53rd European Society of Human Genetics Conference; Viena; Austria; 2020; 189-189
1018-4813
1476-5438
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41431-020-00739-z
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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