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Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth‐plate development. Alterations of different genes of this network may result in overlapping phenotype...

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Autores principales: Elli, Francesca Marta, Mattinzoli, Deborah, Lucca, Camilla, Piu, Matteo, Maffini, Maria A., Costanza, Jole, Fontana, Laura, Santaniello, Carlo, Forino, Concetta, Milani, Donatella, Bonati, Maria Teresa, Secco, Andrea, Gastaldi, Roberto, Alfieri, Carlo, Messa, Piergiorgio, Miozzo, Monica, Arosio, Maura, Mantovani, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305952/
https://www.ncbi.nlm.nih.gov/pubmed/34897794
http://dx.doi.org/10.1002/jbmr.4490
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author Elli, Francesca Marta
Mattinzoli, Deborah
Lucca, Camilla
Piu, Matteo
Maffini, Maria A.
Costanza, Jole
Fontana, Laura
Santaniello, Carlo
Forino, Concetta
Milani, Donatella
Bonati, Maria Teresa
Secco, Andrea
Gastaldi, Roberto
Alfieri, Carlo
Messa, Piergiorgio
Miozzo, Monica
Arosio, Maura
Mantovani, Giovanna
author_facet Elli, Francesca Marta
Mattinzoli, Deborah
Lucca, Camilla
Piu, Matteo
Maffini, Maria A.
Costanza, Jole
Fontana, Laura
Santaniello, Carlo
Forino, Concetta
Milani, Donatella
Bonati, Maria Teresa
Secco, Andrea
Gastaldi, Roberto
Alfieri, Carlo
Messa, Piergiorgio
Miozzo, Monica
Arosio, Maura
Mantovani, Giovanna
author_sort Elli, Francesca Marta
collection PubMed
description Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth‐plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone‐related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)‐like skeletal malformations without a clear clinical diagnosis were analyzed by whole‐exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho‐rhino‐phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)‐binding zinc‐containing domain) and Ikaros‐like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO‐like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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spelling pubmed-93059522022-07-28 Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly Elli, Francesca Marta Mattinzoli, Deborah Lucca, Camilla Piu, Matteo Maffini, Maria A. Costanza, Jole Fontana, Laura Santaniello, Carlo Forino, Concetta Milani, Donatella Bonati, Maria Teresa Secco, Andrea Gastaldi, Roberto Alfieri, Carlo Messa, Piergiorgio Miozzo, Monica Arosio, Maura Mantovani, Giovanna J Bone Miner Res Original Articles Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth‐plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone‐related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)‐like skeletal malformations without a clear clinical diagnosis were analyzed by whole‐exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho‐rhino‐phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)‐binding zinc‐containing domain) and Ikaros‐like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO‐like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). John Wiley & Sons, Inc. 2022-01-17 2022-03 /pmc/articles/PMC9305952/ /pubmed/34897794 http://dx.doi.org/10.1002/jbmr.4490 Text en © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Elli, Francesca Marta
Mattinzoli, Deborah
Lucca, Camilla
Piu, Matteo
Maffini, Maria A.
Costanza, Jole
Fontana, Laura
Santaniello, Carlo
Forino, Concetta
Milani, Donatella
Bonati, Maria Teresa
Secco, Andrea
Gastaldi, Roberto
Alfieri, Carlo
Messa, Piergiorgio
Miozzo, Monica
Arosio, Maura
Mantovani, Giovanna
Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title_full Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title_fullStr Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title_full_unstemmed Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title_short Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly
title_sort novel pathogenetic variants in pthlh and trps1 genes causing syndromic brachydactyly
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305952/
https://www.ncbi.nlm.nih.gov/pubmed/34897794
http://dx.doi.org/10.1002/jbmr.4490
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