Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorROCHA-BRAZ, Manuela G. M.
dc.contributor.authorFRANCA, Monica M.
dc.contributor.authorFERNANDES, Adriana M.
dc.contributor.authorLERARIO, Antonio M.
dc.contributor.authorZANARDO, Evelin A.
dc.contributor.authorSANTANA, Lucas S. de
dc.contributor.authorKULIKOWSKI, Leslie D.
dc.contributor.authorMARTIN, Regina M.
dc.contributor.authorMENDONCA, Berenice B.
dc.contributor.authorFERRAZ-DE-SOUZA, Bruno
dc.date.accessioned2022-02-24T17:13:35Z
dc.date.available2022-02-24T17:13:35Z
dc.date.issued2020
dc.description.abstractContext: The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective: We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design: Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting: Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure: The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results: Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions: While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.eng
dc.description.indexPubMedeng
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/021628, 2011/12696-4]
dc.description.sponsorshipCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
dc.identifier.citationJOURNAL OF THE ENDOCRINE SOCIETY, v.4, n.12, 2020
dc.identifier.doi10.1210/jendso/bvaa148
dc.identifier.eissn2472-1972
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/44369
dc.language.isoeng
dc.publisherENDOCRINE SOCeng
dc.relation.ispartofJournal of the Endocrine Society
dc.rightsopenAccesseng
dc.rights.holderCopyright ENDOCRINE SOCeng
dc.subjectidiopathic osteoporosiseng
dc.subjectfamilial osteoporosiseng
dc.subjectbone fragilityeng
dc.subjectgenetic analysiseng
dc.subjectcandidate geneseng
dc.subjecttargeted massively parallel sequencingeng
dc.subject.otherbone-mineral densityeng
dc.subject.othergenome-wide associationeng
dc.subject.othersequence variantseng
dc.subject.otheri collageneng
dc.subject.othermutationseng
dc.subject.otheridentificationeng
dc.subject.otherlocieng
dc.subject.otherlrp5eng
dc.subject.othersubstitutioneng
dc.subject.otherfractureseng
dc.subject.wosEndocrinology & Metabolismeng
dc.titleComprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosiseng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryisous
hcfmusp.author.externalFRANCA, Monica M.:Univ Sao Paulo, Hosp Clin, Lab Hormonios & Genet Mol LIM 42, Div Endocrinol,Fac Med,HCFMUSP, BR-05403000 Sao Paulo, Brazil; Univ Chicago, Dept Med, Sect Endocrinol, Chicago, IL 60637 USA
hcfmusp.citation.scopus11
hcfmusp.contributor.author-fmusphcMANUELA GIULIANI MARCONDES ROCHA BRAZ
hcfmusp.contributor.author-fmusphcADRIANA MARTINS FERNANDES
hcfmusp.contributor.author-fmusphcANTONIO MARCONDES LERARIO
hcfmusp.contributor.author-fmusphcEVELIN ALINE ZANARDO
hcfmusp.contributor.author-fmusphcLUCAS SANTOS DE SANTANA
hcfmusp.contributor.author-fmusphcLESLIE DOMENICI KULIKOWSKI
hcfmusp.contributor.author-fmusphcREGINA MATSUNAGA MARTIN
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcBRUNO FERRAZ DE SOUZA
hcfmusp.description.issue12
hcfmusp.description.volume4
hcfmusp.origemWOS
hcfmusp.origem.pubmed33195954
hcfmusp.origem.scopus2-s2.0-85096623420
hcfmusp.origem.wosWOS:000734656700002
hcfmusp.publisher.cityWASHINGTONeng
hcfmusp.publisher.countryUSAeng
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