Whole exome sequencing reveals potentially pathogenic variants in a small subset of premenopausal women with idiopathic osteoporosis.

Autor: Cohen A; Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA. Electronic address: ac1044@columbia.edu., Hostyk J; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA., Baugh EH; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA., Buchovecky CM; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA., Aggarwal VS; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA., Recker RR; Department of Medicine, Creighton University Medical Center, Omaha, NE, USA., Lappe JM; Department of Medicine, Creighton University Medical Center, Omaha, NE, USA., Dempster DW; Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA., Zhou H; Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA., Kamanda-Kosseh M; Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA., Bucovsky M; Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA., Stubby J; Department of Medicine, Creighton University Medical Center, Omaha, NE, USA., Goldstein DB; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA., Shane E; Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA.
Jazyk: angličtina
Zdroj: Bone [Bone] 2022 Jan; Vol. 154, pp. 116253. Date of Electronic Publication: 2021 Nov 04.
DOI: 10.1016/j.bone.2021.116253
Abstrakt: Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20-49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous. Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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