| Full text | |
| Author(s): |
Rocha-Braz, Manuela G. M.
[1]
;
Franca, Monica M.
[2, 3]
;
Fernandes, Adriana M.
[1]
;
Lerario, Antonio M.
[4, 5]
;
Zanardo, Evelin A.
[6]
;
de Santana, Lucas S.
[1]
;
Kulikowski, Leslie D.
[6]
;
Martin, Regina M.
[2]
;
Mendonca, Berenice B.
[4]
;
Ferraz-de-Souza, Bruno
[1]
Total Authors: 10
|
| Affiliation: | [1] Univ Sao Paulo, Hosp Clin, Lab Endocrinol Celular & Mol LIM 25, Div Endocrinol, HCFMUSP, Av Dr Arnaldo, 455 Sala 4344 LIM 25, BR-01246903 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Hosp Clin, Lab Hormonios & Genet Mol LIM 42, Div Endocrinol, Fac Med, HCFMUSP, BR-05403000 Sao Paulo - Brazil
[3] Univ Chicago, Dept Med, Sect Endocrinol, Chicago, IL 60637 - USA
[4] Univ Sao Paulo, Fac Med, Lab Sequenciamento Larga Escala SELA, BR-01246903 Sao Paulo, SP - Brazil
[5] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48106 - USA
[6] Univ Sao Paulo, FMUSP, Dept Patol, Lab Citogenom, Fac Med, BR-05403000 Sao Paulo - Brazil
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | JOURNAL OF THE ENDOCRINE SOCIETY; v. 4, n. 12 DEC 2021. |
| Web of Science Citations: | 4 |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 11/12696-4 - Functional genomic analysis of the transcriptional regulation by nuclear receptors in hereditary Vitamin D resistant rickets |
| Grantee: | Bruno Ferraz de Souza |
| Support Opportunities: | Research Grants - Young Investigators Grants |