Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic

Autores
Marsili, Luca; Duque, Kevin R.; Abanto, Jesus; Chinchihualpa Paredes, Nathaly O.; Duker, Andrew P.; Collins, Kathleen; Miranda, Marcelo; Bustamante, M. Leonor; Pauciulo, Michael; Dixon, Michael; Chaib, Hassan; Perez Maturo, Josefina; Hill, Emily J.; Espay, Alberto J.; Kauffman, Marcelo Andres
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.
Fil: Marsili, Luca. University of Cincinnati; Estados Unidos
Fil: Duque, Kevin R.. University of Cincinnati; Estados Unidos
Fil: Abanto, Jesus. University of Cincinnati; Estados Unidos
Fil: Chinchihualpa Paredes, Nathaly O.. University of Cincinnati; Estados Unidos
Fil: Duker, Andrew P.. University of Cincinnati; Estados Unidos
Fil: Collins, Kathleen. Children’s Hospital Medical Center; Estados Unidos
Fil: Miranda, Marcelo. Clinica MEDS; Chile. Fundación Diagnosis; Chile
Fil: Bustamante, M. Leonor. Fundación Diagnosis; Chile. Clinica MEDS; Chile. Universidad de Chile; Chile
Fil: Pauciulo, Michael. Children’s Hospital Medical Center; Estados Unidos
Fil: Dixon, Michael. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados Unidos
Fil: Chaib, Hassan. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados Unidos
Fil: Perez Maturo, Josefina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
Fil: Hill, Emily J.. University of Cincinnati; Estados Unidos
Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos
Fil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
Materia
Movement disorders
Genomics
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/276127
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic ClinicMarsili, LucaDuque, Kevin R.Abanto, JesusChinchihualpa Paredes, Nathaly O.Duker, Andrew P.Collins, KathleenMiranda, MarceloBustamante, M. LeonorPauciulo, MichaelDixon, MichaelChaib, HassanPerez Maturo, JosefinaHill, Emily J.Espay, Alberto J.Kauffman, Marcelo AndresMovement disordersGenomicshttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.Fil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Duque, Kevin R.. University of Cincinnati; Estados UnidosFil: Abanto, Jesus. University of Cincinnati; Estados UnidosFil: Chinchihualpa Paredes, Nathaly O.. University of Cincinnati; Estados UnidosFil: Duker, Andrew P.. University of Cincinnati; Estados UnidosFil: Collins, Kathleen. Children’s Hospital Medical Center; Estados UnidosFil: Miranda, Marcelo. Clinica MEDS; Chile. Fundación Diagnosis; ChileFil: Bustamante, M. Leonor. Fundación Diagnosis; Chile. Clinica MEDS; Chile. Universidad de Chile; ChileFil: Pauciulo, Michael. Children’s Hospital Medical Center; Estados UnidosFil: Dixon, Michael. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados UnidosFil: Chaib, Hassan. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados UnidosFil: Perez Maturo, Josefina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Hill, Emily J.. University of Cincinnati; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaMultidisciplinary Digital Publishing Institute2024-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/276127Marsili, Luca; Duque, Kevin R.; Abanto, Jesus; Chinchihualpa Paredes, Nathaly O.; Duker, Andrew P.; et al.; Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic; Multidisciplinary Digital Publishing Institute; Biomedicines; 12; 12; 11-2024; 1-132227-9059CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2227-9059/12/12/2673info:eu-repo/semantics/altIdentifier/doi/10.3390/biomedicines12122673info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-03-31T15:28:08Zoai:ri.conicet.gov.ar:11336/276127instacron: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:34982026-03-31 15:28:08.633CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
title Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
spellingShingle Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
Marsili, Luca
Movement disorders
Genomics
title_short Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
title_full Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
title_fullStr Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
title_full_unstemmed Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
title_sort Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic
dc.creator.none.fl_str_mv Marsili, Luca
Duque, Kevin R.
Abanto, Jesus
Chinchihualpa Paredes, Nathaly O.
Duker, Andrew P.
Collins, Kathleen
Miranda, Marcelo
Bustamante, M. Leonor
Pauciulo, Michael
Dixon, Michael
Chaib, Hassan
Perez Maturo, Josefina
Hill, Emily J.
Espay, Alberto J.
Kauffman, Marcelo Andres
author Marsili, Luca
author_facet Marsili, Luca
Duque, Kevin R.
Abanto, Jesus
Chinchihualpa Paredes, Nathaly O.
Duker, Andrew P.
Collins, Kathleen
Miranda, Marcelo
Bustamante, M. Leonor
Pauciulo, Michael
Dixon, Michael
Chaib, Hassan
Perez Maturo, Josefina
Hill, Emily J.
Espay, Alberto J.
Kauffman, Marcelo Andres
author_role author
author2 Duque, Kevin R.
Abanto, Jesus
Chinchihualpa Paredes, Nathaly O.
Duker, Andrew P.
Collins, Kathleen
Miranda, Marcelo
Bustamante, M. Leonor
Pauciulo, Michael
Dixon, Michael
Chaib, Hassan
Perez Maturo, Josefina
Hill, Emily J.
Espay, Alberto J.
Kauffman, Marcelo Andres
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Movement disorders
Genomics
topic Movement disorders
Genomics
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.
Fil: Marsili, Luca. University of Cincinnati; Estados Unidos
Fil: Duque, Kevin R.. University of Cincinnati; Estados Unidos
Fil: Abanto, Jesus. University of Cincinnati; Estados Unidos
Fil: Chinchihualpa Paredes, Nathaly O.. University of Cincinnati; Estados Unidos
Fil: Duker, Andrew P.. University of Cincinnati; Estados Unidos
Fil: Collins, Kathleen. Children’s Hospital Medical Center; Estados Unidos
Fil: Miranda, Marcelo. Clinica MEDS; Chile. Fundación Diagnosis; Chile
Fil: Bustamante, M. Leonor. Fundación Diagnosis; Chile. Clinica MEDS; Chile. Universidad de Chile; Chile
Fil: Pauciulo, Michael. Children’s Hospital Medical Center; Estados Unidos
Fil: Dixon, Michael. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados Unidos
Fil: Chaib, Hassan. University of Cincinnati; Estados Unidos. Children’s Hospital Medical Center; Estados Unidos
Fil: Perez Maturo, Josefina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
Fil: Hill, Emily J.. University of Cincinnati; Estados Unidos
Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos
Fil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
description Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.
publishDate 2024
dc.date.none.fl_str_mv 2024-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/276127
Marsili, Luca; Duque, Kevin R.; Abanto, Jesus; Chinchihualpa Paredes, Nathaly O.; Duker, Andrew P.; et al.; Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic; Multidisciplinary Digital Publishing Institute; Biomedicines; 12; 12; 11-2024; 1-13
2227-9059
CONICET Digital
CONICET
url http://hdl.handle.net/11336/276127
identifier_str_mv Marsili, Luca; Duque, Kevin R.; Abanto, Jesus; Chinchihualpa Paredes, Nathaly O.; Duker, Andrew P.; et al.; Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic; Multidisciplinary Digital Publishing Institute; Biomedicines; 12; 12; 11-2024; 1-13
2227-9059
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://www.mdpi.com/2227-9059/12/12/2673
info:eu-repo/semantics/altIdentifier/doi/10.3390/biomedicines12122673
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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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score 12.822162

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