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More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A

BACKGROUND: Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprote...

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Autores principales: Caetano da Silva, Caroline, Ricquebourg, Manon, Orcel, Philippe, Fabre, Stéphanie, Funck‐Brentano, Thomas, Cohen‐Solal, Martine, Collet, Corinne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222848/
https://www.ncbi.nlm.nih.gov/pubmed/33939331
http://dx.doi.org/10.1002/mgg3.1681
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author Caetano da Silva, Caroline
Ricquebourg, Manon
Orcel, Philippe
Fabre, Stéphanie
Funck‐Brentano, Thomas
Cohen‐Solal, Martine
Collet, Corinne
author_facet Caetano da Silva, Caroline
Ricquebourg, Manon
Orcel, Philippe
Fabre, Stéphanie
Funck‐Brentano, Thomas
Cohen‐Solal, Martine
Collet, Corinne
author_sort Caetano da Silva, Caroline
collection PubMed
description BACKGROUND: Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. METHOD AND RESULTS: We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. CONCLUSION: Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility.
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spelling pubmed-82228482021-06-29 More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A Caetano da Silva, Caroline Ricquebourg, Manon Orcel, Philippe Fabre, Stéphanie Funck‐Brentano, Thomas Cohen‐Solal, Martine Collet, Corinne Mol Genet Genomic Med Original Articles BACKGROUND: Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. METHOD AND RESULTS: We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. CONCLUSION: Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility. John Wiley and Sons Inc. 2021-05-03 /pmc/articles/PMC8222848/ /pubmed/33939331 http://dx.doi.org/10.1002/mgg3.1681 Text en © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Caetano da Silva, Caroline
Ricquebourg, Manon
Orcel, Philippe
Fabre, Stéphanie
Funck‐Brentano, Thomas
Cohen‐Solal, Martine
Collet, Corinne
More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title_full More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title_fullStr More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title_full_unstemmed More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title_short More severe phenotype of early‐onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A
title_sort more severe phenotype of early‐onset osteoporosis associated with recessive form of lrp5 and combination with dkk1 or wnt3a
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222848/
https://www.ncbi.nlm.nih.gov/pubmed/33939331
http://dx.doi.org/10.1002/mgg3.1681
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