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Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome

Sotos syndrome is a rare genetic disorder caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain containing protein 1) gene. No clinical diagnostic consensus criteria are published yet, and molecular analysis reduces the clinical diagnostic uncertainty. We screened 1530 unrela...

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Autores principales: Testa, Barbara, Conteduca, Giuseppina, Grasso, Marina, Cecconi, Massimiliano, Lantieri, Francesca, Baldo, Chiara, Arado, Alessia, Andraghetti, Laura, Malacarne, Michela, Milani, Donatella, Coviello, Domenico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956575/
https://www.ncbi.nlm.nih.gov/pubmed/36833222
http://dx.doi.org/10.3390/genes14020295
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author Testa, Barbara
Conteduca, Giuseppina
Grasso, Marina
Cecconi, Massimiliano
Lantieri, Francesca
Baldo, Chiara
Arado, Alessia
Andraghetti, Laura
Malacarne, Michela
Milani, Donatella
Coviello, Domenico
author_facet Testa, Barbara
Conteduca, Giuseppina
Grasso, Marina
Cecconi, Massimiliano
Lantieri, Francesca
Baldo, Chiara
Arado, Alessia
Andraghetti, Laura
Malacarne, Michela
Milani, Donatella
Coviello, Domenico
author_sort Testa, Barbara
collection PubMed
description Sotos syndrome is a rare genetic disorder caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain containing protein 1) gene. No clinical diagnostic consensus criteria are published yet, and molecular analysis reduces the clinical diagnostic uncertainty. We screened 1530 unrelated patients enrolled from 2003 to 2021 at Galliera Hospital and Gaslini Institute in Genoa. NSD1 variants were identified in 292 patients including nine partial gene deletions, 13 microdeletions of the entire NSD1 gene, and 115 novel intragenic variants never previously described. Thirty-two variants of uncertain significance (VUS) out of 115 identified were re-classified. Twenty-five missense NSD1 VUS (25/32, 78.1%) changed class to likely pathogenic or likely benign, showing a highly significant shift in class (p < 0.01). Apart from NSD1, we identified variants in additional genes (NFIX, PTEN, EZH2, TCF20, BRWD3, PPP2R5D) in nine patients analyzed by the NGS custom panel. We describe the evolution of diagnostic techniques in our laboratory to ascertain molecular diagnosis, the identification of 115 new variants, and the re-classification of 25 VUS in NSD1. We underline the utility of sharing variant classification and the need to improve communication between the laboratory staff and the referring physician.
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spelling pubmed-99565752023-02-25 Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome Testa, Barbara Conteduca, Giuseppina Grasso, Marina Cecconi, Massimiliano Lantieri, Francesca Baldo, Chiara Arado, Alessia Andraghetti, Laura Malacarne, Michela Milani, Donatella Coviello, Domenico Genes (Basel) Article Sotos syndrome is a rare genetic disorder caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain containing protein 1) gene. No clinical diagnostic consensus criteria are published yet, and molecular analysis reduces the clinical diagnostic uncertainty. We screened 1530 unrelated patients enrolled from 2003 to 2021 at Galliera Hospital and Gaslini Institute in Genoa. NSD1 variants were identified in 292 patients including nine partial gene deletions, 13 microdeletions of the entire NSD1 gene, and 115 novel intragenic variants never previously described. Thirty-two variants of uncertain significance (VUS) out of 115 identified were re-classified. Twenty-five missense NSD1 VUS (25/32, 78.1%) changed class to likely pathogenic or likely benign, showing a highly significant shift in class (p < 0.01). Apart from NSD1, we identified variants in additional genes (NFIX, PTEN, EZH2, TCF20, BRWD3, PPP2R5D) in nine patients analyzed by the NGS custom panel. We describe the evolution of diagnostic techniques in our laboratory to ascertain molecular diagnosis, the identification of 115 new variants, and the re-classification of 25 VUS in NSD1. We underline the utility of sharing variant classification and the need to improve communication between the laboratory staff and the referring physician. MDPI 2023-01-22 /pmc/articles/PMC9956575/ /pubmed/36833222 http://dx.doi.org/10.3390/genes14020295 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Testa, Barbara
Conteduca, Giuseppina
Grasso, Marina
Cecconi, Massimiliano
Lantieri, Francesca
Baldo, Chiara
Arado, Alessia
Andraghetti, Laura
Malacarne, Michela
Milani, Donatella
Coviello, Domenico
Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title_full Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title_fullStr Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title_full_unstemmed Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title_short Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome
title_sort molecular analysis and reclassification of nsd1 gene variants in a cohort of patients with clinical suspicion of sotos syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956575/
https://www.ncbi.nlm.nih.gov/pubmed/36833222
http://dx.doi.org/10.3390/genes14020295
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