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Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS)
Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that all...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090705/ http://dx.doi.org/10.1210/jendso/bvab048.1397 |
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author | Toni, Ledjona Plachy, Lukas Dusatkova, Petra Elblova, Lenka Amaratunga, Shenali Anne Kolouskova, Stanislava Obermannova, Barbora Snajderova, Marta Sumnik, Zdenek Pruhova, Stepanka Lebl, Jan |
author_facet | Toni, Ledjona Plachy, Lukas Dusatkova, Petra Elblova, Lenka Amaratunga, Shenali Anne Kolouskova, Stanislava Obermannova, Barbora Snajderova, Marta Sumnik, Zdenek Pruhova, Stepanka Lebl, Jan |
author_sort | Toni, Ledjona |
collection | PubMed |
description | Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120. |
format | Online Article Text |
id | pubmed-8090705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-80907052021-05-12 Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) Toni, Ledjona Plachy, Lukas Dusatkova, Petra Elblova, Lenka Amaratunga, Shenali Anne Kolouskova, Stanislava Obermannova, Barbora Snajderova, Marta Sumnik, Zdenek Pruhova, Stepanka Lebl, Jan J Endocr Soc Pediatric Endocrinology Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120. Oxford University Press 2021-05-03 /pmc/articles/PMC8090705/ http://dx.doi.org/10.1210/jendso/bvab048.1397 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Pediatric Endocrinology Toni, Ledjona Plachy, Lukas Dusatkova, Petra Elblova, Lenka Amaratunga, Shenali Anne Kolouskova, Stanislava Obermannova, Barbora Snajderova, Marta Sumnik, Zdenek Pruhova, Stepanka Lebl, Jan Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title | Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title_full | Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title_fullStr | Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title_full_unstemmed | Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title_short | Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS) |
title_sort | stratifying the genetic aetiology in children born small for gestational age with persistent short stature (sga-ss) |
topic | Pediatric Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090705/ http://dx.doi.org/10.1210/jendso/bvab048.1397 |
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