Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis.
J Endocr Soc
; 4(12): bvaa148, 2020 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-33195954
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 ANDSETTING:
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 OUTCOMEMEASURE:
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.
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Banco de datos:
MEDLINE
Tipo de estudio:
Risk_factors_studies
Idioma:
En
Revista:
J Endocr Soc
Año:
2020
Tipo del documento:
Article
País de afiliación:
Brasil