Variants of uncertain significance (VUS) model show

Autores
Carcione, María Micaela; Mazzanti, Chiara; Luce, Leonela Natalia; Giliberto, Florencia
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Muscular Dystrophies (MD) are a group of rare inherited diseases that cause weakness and progressive degeneration of muscle tissue. The clinical symptoms of these pathologies overlap, hindering differential diagnosis, which is of paramount importance to establish the standard of care. Among them, Dystrophinopathies are the most prevalent type of MD and are caused by mutations in the DMD gene. Genetic or molecular studies are the gold standard for reaching a MD differential diagnosis, for which molecular alterations in MD associated genes can be detected by Whole Exome Sequencing (WES). One of the major challenges of the Next Generation Sequencing (NGS) data interpretation is the occurrence of Variants of Uncertain Significance (VUS). The present work aims to provide a thorough strategy to analyze the effect of VUS, applying different predictive software, conservation/evolutionary and protein modeling tools. A cohort of 141 patients with presumptive clinical diagnosis of dystrophinopathy and negative MLPA result was analyzed by WES. We deepened the screening to all the MD associated genes included in the Gene Table of Neuromuscular Disorders. In a subset of 6 individuals, we detected VUS in the following genes: DMD (2/6), FKRP (2/6) and POMT2 (2/6). We implemented several predictive software to analyze the effect of VUS, and UCSF ChimeraX for protein modeling. Also, in one case, we could do a segregation analysis of the variants. The implemented strategy provided new insights to predict more accurately the effect of the identified sequence variants and even reclassified them. Finally, this work provides alternative approaches for the analysis of sequence variants, especially when functional studies are not possible to be carried out, to determine the effect of VUS.
Fil: Carcione, María Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Mazzanti, Chiara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Luce, Leonela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Giliberto, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
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
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
Materia
VARIANTS OF UNCERTAIN SIGNIFICANCE
Muscular Dystrophies
molecular studies
differential diagnosis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/223701
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Variants of uncertain significance (VUS) model showCarcione, María MicaelaMazzanti, ChiaraLuce, Leonela NataliaGiliberto, FlorenciaVARIANTS OF UNCERTAIN SIGNIFICANCEMuscular Dystrophiesmolecular studiesdifferential diagnosishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Muscular Dystrophies (MD) are a group of rare inherited diseases that cause weakness and progressive degeneration of muscle tissue. The clinical symptoms of these pathologies overlap, hindering differential diagnosis, which is of paramount importance to establish the standard of care. Among them, Dystrophinopathies are the most prevalent type of MD and are caused by mutations in the DMD gene. Genetic or molecular studies are the gold standard for reaching a MD differential diagnosis, for which molecular alterations in MD associated genes can be detected by Whole Exome Sequencing (WES). One of the major challenges of the Next Generation Sequencing (NGS) data interpretation is the occurrence of Variants of Uncertain Significance (VUS). The present work aims to provide a thorough strategy to analyze the effect of VUS, applying different predictive software, conservation/evolutionary and protein modeling tools. A cohort of 141 patients with presumptive clinical diagnosis of dystrophinopathy and negative MLPA result was analyzed by WES. We deepened the screening to all the MD associated genes included in the Gene Table of Neuromuscular Disorders. In a subset of 6 individuals, we detected VUS in the following genes: DMD (2/6), FKRP (2/6) and POMT2 (2/6). We implemented several predictive software to analyze the effect of VUS, and UCSF ChimeraX for protein modeling. Also, in one case, we could do a segregation analysis of the variants. The implemented strategy provided new insights to predict more accurately the effect of the identified sequence variants and even reclassified them. Finally, this work provides alternative approaches for the analysis of sequence variants, especially when functional studies are not possible to be carried out, to determine the effect of VUS.Fil: Carcione, María Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Mazzanti, Chiara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Luce, Leonela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Giliberto, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaLXV 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 FisiologíaBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaFundación Revista Medicina2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/223701Variants of uncertain significance (VUS) model show; 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; Buenos Aires; Argentina; 2020; 72-730025-7680CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol80-20/s5/Mv80s5.pdfInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:10:21Zoai:ri.conicet.gov.ar:11336/223701instacron: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:34982025-09-29 10:10:21.77CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Variants of uncertain significance (VUS) model show
title Variants of uncertain significance (VUS) model show
spellingShingle Variants of uncertain significance (VUS) model show
Carcione, María Micaela
VARIANTS OF UNCERTAIN SIGNIFICANCE
Muscular Dystrophies
molecular studies
differential diagnosis
title_short Variants of uncertain significance (VUS) model show
title_full Variants of uncertain significance (VUS) model show
title_fullStr Variants of uncertain significance (VUS) model show
title_full_unstemmed Variants of uncertain significance (VUS) model show
title_sort Variants of uncertain significance (VUS) model show
dc.creator.none.fl_str_mv Carcione, María Micaela
Mazzanti, Chiara
Luce, Leonela Natalia
Giliberto, Florencia
author Carcione, María Micaela
author_facet Carcione, María Micaela
Mazzanti, Chiara
Luce, Leonela Natalia
Giliberto, Florencia
author_role author
author2 Mazzanti, Chiara
Luce, Leonela Natalia
Giliberto, Florencia
author2_role author
author
author
dc.subject.none.fl_str_mv VARIANTS OF UNCERTAIN SIGNIFICANCE
Muscular Dystrophies
molecular studies
differential diagnosis
topic VARIANTS OF UNCERTAIN SIGNIFICANCE
Muscular Dystrophies
molecular studies
differential diagnosis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Muscular Dystrophies (MD) are a group of rare inherited diseases that cause weakness and progressive degeneration of muscle tissue. The clinical symptoms of these pathologies overlap, hindering differential diagnosis, which is of paramount importance to establish the standard of care. Among them, Dystrophinopathies are the most prevalent type of MD and are caused by mutations in the DMD gene. Genetic or molecular studies are the gold standard for reaching a MD differential diagnosis, for which molecular alterations in MD associated genes can be detected by Whole Exome Sequencing (WES). One of the major challenges of the Next Generation Sequencing (NGS) data interpretation is the occurrence of Variants of Uncertain Significance (VUS). The present work aims to provide a thorough strategy to analyze the effect of VUS, applying different predictive software, conservation/evolutionary and protein modeling tools. A cohort of 141 patients with presumptive clinical diagnosis of dystrophinopathy and negative MLPA result was analyzed by WES. We deepened the screening to all the MD associated genes included in the Gene Table of Neuromuscular Disorders. In a subset of 6 individuals, we detected VUS in the following genes: DMD (2/6), FKRP (2/6) and POMT2 (2/6). We implemented several predictive software to analyze the effect of VUS, and UCSF ChimeraX for protein modeling. Also, in one case, we could do a segregation analysis of the variants. The implemented strategy provided new insights to predict more accurately the effect of the identified sequence variants and even reclassified them. Finally, this work provides alternative approaches for the analysis of sequence variants, especially when functional studies are not possible to be carried out, to determine the effect of VUS.
Fil: Carcione, María Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Mazzanti, Chiara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Luce, Leonela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Giliberto, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
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
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
description Muscular Dystrophies (MD) are a group of rare inherited diseases that cause weakness and progressive degeneration of muscle tissue. The clinical symptoms of these pathologies overlap, hindering differential diagnosis, which is of paramount importance to establish the standard of care. Among them, Dystrophinopathies are the most prevalent type of MD and are caused by mutations in the DMD gene. Genetic or molecular studies are the gold standard for reaching a MD differential diagnosis, for which molecular alterations in MD associated genes can be detected by Whole Exome Sequencing (WES). One of the major challenges of the Next Generation Sequencing (NGS) data interpretation is the occurrence of Variants of Uncertain Significance (VUS). The present work aims to provide a thorough strategy to analyze the effect of VUS, applying different predictive software, conservation/evolutionary and protein modeling tools. A cohort of 141 patients with presumptive clinical diagnosis of dystrophinopathy and negative MLPA result was analyzed by WES. We deepened the screening to all the MD associated genes included in the Gene Table of Neuromuscular Disorders. In a subset of 6 individuals, we detected VUS in the following genes: DMD (2/6), FKRP (2/6) and POMT2 (2/6). We implemented several predictive software to analyze the effect of VUS, and UCSF ChimeraX for protein modeling. Also, in one case, we could do a segregation analysis of the variants. The implemented strategy provided new insights to predict more accurately the effect of the identified sequence variants and even reclassified them. Finally, this work provides alternative approaches for the analysis of sequence variants, especially when functional studies are not possible to be carried out, to determine the effect of VUS.
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/11336/223701
Variants of uncertain significance (VUS) model show; 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; Buenos Aires; Argentina; 2020; 72-73
0025-7680
CONICET Digital
CONICET
url http://hdl.handle.net/11336/223701
identifier_str_mv Variants of uncertain significance (VUS) model show; 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; Buenos Aires; Argentina; 2020; 72-73
0025-7680
CONICET Digital
CONICET
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dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol80-20/s5/Mv80s5.pdf
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dc.format.none.fl_str_mv application/pdf
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dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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