Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/60543 |
Resumo: | Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.Design and methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN(n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11(n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.Conclusion: A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification. |
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2023-11-06T22:12:40Z2023-11-06T22:12:40Z2022111211010.1530/ec-22-021420493614http://hdl.handle.net/1843/60543Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.Design and methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN(n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11(n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.Conclusion: A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.engUniversidade Federal de Minas GeraisUFMGBrasilMED - DEPARTAMENTO DE CLÍNICA MÉDICAEndocrine ConnectionsBody HeightGenetic Association StudiesSuppression, GeneticIdiopathic short staturemultigene sequencing analysisGeneticSuppression, GeneticDiagnostic yield of a multigene sequencing approach in children classified as idiopathic short statureinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://doi.org/10.1530/EC-22-0214Nathalia Liberatoscioli MenezesandradeMicheline a r SouzaBruna l FreireAna c v KrepischiCarlos Alberto LonguiAntonio Marcondes LerarioIvo j p ArnholdAlexander a l JorgeGabriela Andrade VasquesMariana Ferreira de Assis FunariAlexsandra Christianne MalaquiasPaulo Ferrez Collett-solbergNathália Lisboa Rosa Almeida GomesRenata ScalcoNaiara Castelo Branco DantasRaissa c RezendeAngelica m f p Tiburcioapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/60543/1/License.txtfa505098d172de0bc8864fc1287ffe22MD51ORIGINALDiagnostic yield of a multigene sequencing pdfa.pdfDiagnostic yield of a multigene sequencing pdfa.pdfapplication/pdf536094https://repositorio.ufmg.br/bitstream/1843/60543/2/Diagnostic%20yield%20of%20a%20multigene%20sequencing%20pdfa.pdfb3e8e09e13ee7802affbbae5622dc24cMD521843/605432023-11-06 20:50:58.683oai:repositorio.ufmg.br:1843/60543Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-11-06T23:50:58Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
title |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
spellingShingle |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature Nathalia Liberatoscioli Menezesandrade Idiopathic short stature multigene sequencing analysis Genetic Suppression, Genetic Body Height Genetic Association Studies Suppression, Genetic |
title_short |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
title_full |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
title_fullStr |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
title_full_unstemmed |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
title_sort |
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature |
author |
Nathalia Liberatoscioli Menezesandrade |
author_facet |
Nathalia Liberatoscioli Menezesandrade Micheline a r Souza Bruna l Freire Ana c v Krepischi Carlos Alberto Longui Antonio Marcondes Lerario Ivo j p Arnhold Alexander a l Jorge Gabriela Andrade Vasques Mariana Ferreira de Assis Funari Alexsandra Christianne Malaquias Paulo Ferrez Collett-solberg Nathália Lisboa Rosa Almeida Gomes Renata Scalco Naiara Castelo Branco Dantas Raissa c Rezende Angelica m f p Tiburcio |
author_role |
author |
author2 |
Micheline a r Souza Bruna l Freire Ana c v Krepischi Carlos Alberto Longui Antonio Marcondes Lerario Ivo j p Arnhold Alexander a l Jorge Gabriela Andrade Vasques Mariana Ferreira de Assis Funari Alexsandra Christianne Malaquias Paulo Ferrez Collett-solberg Nathália Lisboa Rosa Almeida Gomes Renata Scalco Naiara Castelo Branco Dantas Raissa c Rezende Angelica m f p Tiburcio |
author2_role |
author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Nathalia Liberatoscioli Menezesandrade Micheline a r Souza Bruna l Freire Ana c v Krepischi Carlos Alberto Longui Antonio Marcondes Lerario Ivo j p Arnhold Alexander a l Jorge Gabriela Andrade Vasques Mariana Ferreira de Assis Funari Alexsandra Christianne Malaquias Paulo Ferrez Collett-solberg Nathália Lisboa Rosa Almeida Gomes Renata Scalco Naiara Castelo Branco Dantas Raissa c Rezende Angelica m f p Tiburcio |
dc.subject.por.fl_str_mv |
Idiopathic short stature multigene sequencing analysis Genetic Suppression, Genetic |
topic |
Idiopathic short stature multigene sequencing analysis Genetic Suppression, Genetic Body Height Genetic Association Studies Suppression, Genetic |
dc.subject.other.pt_BR.fl_str_mv |
Body Height Genetic Association Studies Suppression, Genetic |
description |
Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.Design and methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN(n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11(n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.Conclusion: A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification. |
publishDate |
2022 |
dc.date.issued.fl_str_mv |
2022 |
dc.date.accessioned.fl_str_mv |
2023-11-06T22:12:40Z |
dc.date.available.fl_str_mv |
2023-11-06T22:12:40Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/60543 |
dc.identifier.doi.pt_BR.fl_str_mv |
10.1530/ec-22-0214 |
dc.identifier.issn.pt_BR.fl_str_mv |
20493614 |
identifier_str_mv |
10.1530/ec-22-0214 20493614 |
url |
http://hdl.handle.net/1843/60543 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
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Endocrine Connections |
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openAccess |
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application/pdf |
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Universidade Federal de Minas Gerais |
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UFMG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
MED - DEPARTAMENTO DE CLÍNICA MÉDICA |
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Universidade Federal de Minas Gerais |
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