Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability

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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.authorDANTAS, Naiara C. B.
dc.contributor.authorFUNARI, Mariana F. A.
dc.contributor.authorLERARIO, Antonio M.
dc.contributor.authorANDRADE, Nathalia L. M.
dc.contributor.authorREZENDE, Raissa C.
dc.contributor.authorCELLIN, Laurana P.
dc.contributor.authorALVES, Cresio
dc.contributor.authorCRISOSTOMO, Lindiane G.
dc.contributor.authorARNHOLD, Ivo J. P.
dc.contributor.authorMENDONCA, Berenice
dc.contributor.authorSCALCO, Renata C.
dc.contributor.authorJORGE, Alexander A. L.
dc.date.accessioned2023-12-15T18:44:31Z
dc.date.available2023-12-15T18:44:31Z
dc.date.issued2023
dc.description.abstractObjective Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature.Design and methods We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants.Results We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04).Conclusion In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.eng
dc.description.indexMEDLINE
dc.description.indexPubMed
dc.description.indexWoS
dc.description.indexScopus
dc.description.sponsorshipThe authors are grateful to all participating patients and their families. We would like to acknowledge the contributions of all personnel at the Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo Medical School, Sao P
dc.description.sponsorshipHospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil
dc.identifier.citationEUROPEAN JOURNAL OF ENDOCRINOLOGY, v.189, n.3, p.387-395, 2023
dc.identifier.doi10.1093/ejendo/lvad128
dc.identifier.eissn1479-683X
dc.identifier.issn0804-4643
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/57310
dc.language.isoeng
dc.publisherOXFORD UNIV PRESSeng
dc.relation.ispartofEuropean Journal of Endocrinology
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright OXFORD UNIV PRESSeng
dc.subjectSHOX deficiencyeng
dc.subjectgenetic modifierseng
dc.subjectphenotype variabilityeng
dc.subjectshort statureeng
dc.subjectgenetic backgroundeng
dc.subject.otheridiopathic short statureeng
dc.subject.otherleri-weill dyschondrosteosiseng
dc.subject.otherpeptide receptor-beng
dc.subject.othernatriuretic peptideeng
dc.subject.othergrowth failureeng
dc.subject.othermutationseng
dc.subject.otherchildreneng
dc.subject.otherhaploinsufficiencyeng
dc.subject.otherdysplasiaeng
dc.subject.otherstandardseng
dc.subject.wosEndocrinology & Metabolismeng
dc.titleIdentification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variabilityeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryisous
hcfmusp.author.externalLERARIO, Antonio M.:Univ Michigan, Dept Internal Med, Div Endocrinol Diabet & Metab, Ann Arbor, MI 48105 USA
hcfmusp.author.externalALVES, Cresio:Univ Fed Bahia, Fac Med, Pediat Endocrinol Unit, Hosp Univ Prof Edgard Santos, BR-400326010 Salvador, BA, Brazil
hcfmusp.author.externalCRISOSTOMO, Lindiane G.:Ctr Univ Sao Camilo, Dept Pediat, BR-04263200 Sao Paulo, SP, Brazil
hcfmusp.citation.scopus0
hcfmusp.contributor.author-fmusphcNAIARA CASTELO BRANCO DANTAS
hcfmusp.contributor.author-fmusphcMARIANA FERREIRA DE ASSIS FUNARI
hcfmusp.contributor.author-fmusphcNATHALIA LIBERATOSCIOLI MENEZES DE ANDRADE
hcfmusp.contributor.author-fmusphcRAISSA CARNEIRO REZENDE
hcfmusp.contributor.author-fmusphcLAURANA DE POLLI CELLIN
hcfmusp.contributor.author-fmusphcIVO JORGE PRADO ARNHOLD
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcRENATA DA CUNHA SCALCO
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.description.beginpage387
hcfmusp.description.endpage395
hcfmusp.description.issue3
hcfmusp.description.volume189
hcfmusp.origemWOS
hcfmusp.origem.pubmed37695807
hcfmusp.origem.scopus2-s2.0-85182908931
hcfmusp.origem.wosWOS:001068733900001
hcfmusp.publisher.cityOXFORDeng
hcfmusp.publisher.countryENGLANDeng
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