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

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art_ROCHA-BRAZ_Comprehensive_Genetic_Analysis_of_128_Candidate_Genes_in_2020.PDF (567.77 KB)
Citações na Scopus
11
Tipo de produção
article
Data de publicação
2020
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ENDOCRINE SOC
Autores
FRANCA, Monica M.
Citação
JOURNAL OF THE ENDOCRINE SOCIETY, v.4, n.12, 2020
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Context: 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.
Palavras-chave
idiopathic osteoporosis, familial osteoporosis, bone fragility, genetic analysis, candidate genes, targeted massively parallel sequencing
URI
https://observatorio.fm.usp.br/handle/OPI/44369
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/03
Artigos e Materiais de Revistas Científicas - LIM/25
Artigos e Materiais de Revistas Científicas - LIM/36
Artigos e Materiais de Revistas Científicas - LIM/42