{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:37:48Z","timestamp":1791041868243,"version":"4.1.0"},"reference-count":38,"publisher":"Bioscientifica","issue":"12","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ec.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield\u2009=\u200916.7%). Three patients had more than one P\/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation:\n                      <jats:italic>IHH<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20094),\n                      <jats:italic>SHOX<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20093),\n                      <jats:italic>FGFR3<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20092),\n                      <jats:italic>NPR2<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20092),\n                      <jats:italic>ACAN<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20092), and\n                      <jats:italic>COL2A1<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20091) or involved in the RAS\/MAPK pathway:\n                      <jats:italic>NF1<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20092),\n                      <jats:italic>PTPN11<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20091),\n                      <jats:italic>CBL<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20091), and\n                      <jats:italic>BRAF<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009\u2009=\u20091). 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 \u2264 or &gt; \u22123;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.034). The genetic diagnosis had an impact on clinical management for four children.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/ec-22-0214","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T07:06:53Z","timestamp":1668409613000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-10","source":"Crossref","is-referenced-by-count":21,"title":["Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature"],"prefix":"10.1530","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1628-7881","authenticated-orcid":true,"given":"Nathalia Liberatoscioli Menezes","family":"Andrade","sequence":"first","affiliation":[{"name":"Unidade de Endocrinologia Genetica (LIM 25), Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo (USP), Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Ferreira de Assis","family":"Funari","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo (USP), Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexsandra Christianne","family":"Malaquias","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria, Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Ferrez","family":"Collett-Solberg","sequence":"additional","affiliation":[{"name":"Disciplina de Endocrinologia, Departamento de Medicina Interna, Faculdade de Ci\u00eancias Medicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia L R A","family":"Gomes","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Unidade de Crescimento, Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Scalco","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo (USP), Sao Paulo, Brasil"},{"name":"Departamento de Medicina, Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiara Castelo Branco","family":"Dantas","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Genetica (LIM 25), Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo (USP), Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-5576","authenticated-orcid":true,"given":"Raissa C","family":"Rezende","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Genetica (LIM 25), Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo (USP), Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica M F P","family":"Tiburcio","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Unidade de Crescimento, Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micheline A R","family":"Souza","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia do Instituto de Puericultura e Pediatria Martagao Gesteira\/Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna L","family":"Freire","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Genetica (LIM 25), Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo (USP), Sao Paulo, Brasil"},{"name":"Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo (USP), Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C V","family":"Krepischi","sequence":"additional","affiliation":[{"name":"Centro de Pesquisa em Genoma Humano e C\u00e9lulas-Tronco, Departamento de Gen\u00e9tica e Biologia Evolutiva, Instituto de Bioci\u00eancias, Universidade de Sao Paulo, S\u00e3o Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Alberto","family":"Longui","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria, Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Marcondes","family":"Lerario","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo J P","family":"Arnhold","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao 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