Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina

Autores
Buonfiglio, Paula Inés; Bruque, Carlos Darío; Lotersztein, Vanesa; Goldschmidt, Ezequiel Darío; Plazas, Paola Viviana; Dalamon, Viviana Karina; Elgoyhen, Ana Belen
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Hereditary hearing loss is the most common sensory disorder affecting 1:500 newborn children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity led us to design a multistep diagnosis strategy with the use of Whole Exome Sequencing Technique (WES). The main objectives were molecular diagnosis of deaf patients and novel genetic variants in-silico and in-vivo analyses.1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing genotyping 25% of them according to worldwide reports. From undiagnosed patients, 29 families were selected to perform WES. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG/Hearing Loss-Expert Panel Standards.Some of the novel variants were further studied in silico by structural, stability and motifs 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 amino-acid changes. Furthermore, knock down phenotype rescue assay in zebrafish is 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 a one novel variant in MYO6 gene which affected the hair cell function and hence, auditory system physiology.This study shows that our algorithm is successful for deafness genetic diagnosis. Comprehensive analysis is crucial to strengthen the pathogenicity effect of variants and discard some of them. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of hereditary hearing loss.
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 Darío. 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: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina
Fil: Goldschmidt, Ezequiel Darío. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; 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
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
Reunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología
Ciudad Autónoma de Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
Materia
Hearing Loss
Genetics
Wes
Analysis
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:11336/201597
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in ArgentinaBuonfiglio, Paula InésBruque, Carlos DaríoLotersztein, VanesaGoldschmidt, Ezequiel DaríoPlazas, Paola VivianaDalamon, Viviana KarinaElgoyhen, Ana BelenHearing LossGeneticsWesAnalysishttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Hereditary hearing loss is the most common sensory disorder affecting 1:500 newborn children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity led us to design a multistep diagnosis strategy with the use of Whole Exome Sequencing Technique (WES). The main objectives were molecular diagnosis of deaf patients and novel genetic variants in-silico and in-vivo analyses.1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing genotyping 25% of them according to worldwide reports. From undiagnosed patients, 29 families were selected to perform WES. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG/Hearing Loss-Expert Panel Standards.Some of the novel variants were further studied in silico by structural, stability and motifs 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 amino-acid changes. Furthermore, knock down phenotype rescue assay in zebrafish is 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 a one novel variant in MYO6 gene which affected the hair cell function and hence, auditory system physiology.This study shows that our algorithm is successful for deafness genetic diagnosis. Comprehensive analysis is crucial to strengthen the pathogenicity effect of variants and discard some of them. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of hereditary hearing loss.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 Darío. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; ArgentinaFil: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Goldschmidt, Ezequiel Darío. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; ArgentinaFil: Dalamon, Viviana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaReunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de FisiologíaCiudad Autónoma de Buenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaFundación Revista MedicinaCarrillo, Maria CristinaTrevani, Analía SilvinaLarocca, Maria Cecilia2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/201597Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina; Reunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 70-700025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol80-20/s5/Mv80s5.pdfInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:25Zoai:ri.conicet.gov.ar:11336/201597instacron: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 10:10:25.309CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
title Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
spellingShingle Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
Buonfiglio, Paula Inés
Hearing Loss
Genetics
Wes
Analysis
title_short Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
title_full Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
title_fullStr Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
title_full_unstemmed Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
title_sort Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina
dc.creator.none.fl_str_mv Buonfiglio, Paula Inés
Bruque, Carlos Darío
Lotersztein, Vanesa
Goldschmidt, Ezequiel Darío
Plazas, Paola Viviana
Dalamon, Viviana Karina
Elgoyhen, Ana Belen
author Buonfiglio, Paula Inés
author_facet Buonfiglio, Paula Inés
Bruque, Carlos Darío
Lotersztein, Vanesa
Goldschmidt, Ezequiel Darío
Plazas, Paola Viviana
Dalamon, Viviana Karina
Elgoyhen, Ana Belen
author_role author
author2 Bruque, Carlos Darío
Lotersztein, Vanesa
Goldschmidt, Ezequiel Darío
Plazas, Paola Viviana
Dalamon, Viviana Karina
Elgoyhen, Ana Belen
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Carrillo, Maria Cristina
Trevani, Analía Silvina
Larocca, Maria Cecilia
dc.subject.none.fl_str_mv Hearing Loss
Genetics
Wes
Analysis
topic Hearing Loss
Genetics
Wes
Analysis
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 is the most common sensory disorder affecting 1:500 newborn children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity led us to design a multistep diagnosis strategy with the use of Whole Exome Sequencing Technique (WES). The main objectives were molecular diagnosis of deaf patients and novel genetic variants in-silico and in-vivo analyses.1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing genotyping 25% of them according to worldwide reports. From undiagnosed patients, 29 families were selected to perform WES. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG/Hearing Loss-Expert Panel Standards.Some of the novel variants were further studied in silico by structural, stability and motifs 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 amino-acid changes. Furthermore, knock down phenotype rescue assay in zebrafish is 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 a one novel variant in MYO6 gene which affected the hair cell function and hence, auditory system physiology.This study shows that our algorithm is successful for deafness genetic diagnosis. Comprehensive analysis is crucial to strengthen the pathogenicity effect of variants and discard some of them. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of hereditary hearing loss.
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 Darío. 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: Lotersztein, Vanesa. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina
Fil: Goldschmidt, Ezequiel Darío. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología. 3º Cátedra de Farmacología; 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
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
Reunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología
Ciudad Autónoma de Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
description Hereditary hearing loss is the most common sensory disorder affecting 1:500 newborn children. It is a heterogeneous disease and more than 100 genes have been related to the pathology. This complexity led us to design a multistep diagnosis strategy with the use of Whole Exome Sequencing Technique (WES). The main objectives were molecular diagnosis of deaf patients and novel genetic variants in-silico and in-vivo analyses.1250 patients were analyzed for frequent mutations in GJB2 and GJB6 genes by Sanger Sequencing genotyping 25% of them according to worldwide reports. From undiagnosed patients, 29 families were selected to perform WES. After filtering and analysis process, 45% of patients were genotyped, identifying 23 causative mutations (11 novel, 12 reported) classified according to ACMG/Hearing Loss-Expert Panel Standards.Some of the novel variants were further studied in silico by structural, stability and motifs 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 amino-acid changes. Furthermore, knock down phenotype rescue assay in zebrafish is 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 a one novel variant in MYO6 gene which affected the hair cell function and hence, auditory system physiology.This study shows that our algorithm is successful for deafness genetic diagnosis. Comprehensive analysis is crucial to strengthen the pathogenicity effect of variants and discard some of them. These findings highlight the importance of genetic studies followed by in silico and in vivo validation to better understand the genetic basis of hereditary hearing loss.
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
Reunión
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/11336/201597
Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina; Reunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 70-70
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/201597
identifier_str_mv Comprehensive analysis of genetic variants identified by Whole Exome Sequencing in hearing impaired patients in Argentina; Reunión Anual de Sociedades de Biociencia 2020; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de Fisiología; Ciudad Autónoma de Buenos Aires; Argentina; 2020; 70-70
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol80-20/s5/Mv80s5.pdf
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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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