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The variability of SMCHD1 gene in FSHD patients: evidence of new mutations

In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4...

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Autores principales: Strafella, Claudia, Caputo, Valerio, Galota, Rosaria Maria, Campoli, Giulia, Bax, Cristina, Colantoni, Luca, Minozzi, Giulietta, Orsini, Chiara, Politano, Luisa, Tasca, Giorgio, Novelli, Giuseppe, Ricci, Enzo, Giardina, Emiliano, Cascella, Raffaella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969370/
https://www.ncbi.nlm.nih.gov/pubmed/31600781
http://dx.doi.org/10.1093/hmg/ddz239
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author Strafella, Claudia
Caputo, Valerio
Galota, Rosaria Maria
Campoli, Giulia
Bax, Cristina
Colantoni, Luca
Minozzi, Giulietta
Orsini, Chiara
Politano, Luisa
Tasca, Giorgio
Novelli, Giuseppe
Ricci, Enzo
Giardina, Emiliano
Cascella, Raffaella
author_facet Strafella, Claudia
Caputo, Valerio
Galota, Rosaria Maria
Campoli, Giulia
Bax, Cristina
Colantoni, Luca
Minozzi, Giulietta
Orsini, Chiara
Politano, Luisa
Tasca, Giorgio
Novelli, Giuseppe
Ricci, Enzo
Giardina, Emiliano
Cascella, Raffaella
author_sort Strafella, Claudia
collection PubMed
description In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1–7 RU, borderline: 8-10RU and normal fragment: >11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3’untranslated region (3′UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs(*)48), c.2129dupC (p.A711Cfs(*)11), c.3469G>T (p.G1157(*)), c.5150_5151delAA (p.K1717Rfs(*)16) and c.1131+2_1131+5delTAAG, c.3010A>T (p.K1004(*)), c.853G>C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.(*)1376A>C, rs7238459; c.(*)1579G>A, rs559994; c.(*)1397A>G, rs150573037; c.(*)1631C>T, rs193227855; c.(*)1889G>C, rs149259359) were identified in the 3′UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype–phenotype correlations.
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spelling pubmed-69693702020-01-23 The variability of SMCHD1 gene in FSHD patients: evidence of new mutations Strafella, Claudia Caputo, Valerio Galota, Rosaria Maria Campoli, Giulia Bax, Cristina Colantoni, Luca Minozzi, Giulietta Orsini, Chiara Politano, Luisa Tasca, Giorgio Novelli, Giuseppe Ricci, Enzo Giardina, Emiliano Cascella, Raffaella Hum Mol Genet General Article In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1–7 RU, borderline: 8-10RU and normal fragment: >11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3’untranslated region (3′UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs(*)48), c.2129dupC (p.A711Cfs(*)11), c.3469G>T (p.G1157(*)), c.5150_5151delAA (p.K1717Rfs(*)16) and c.1131+2_1131+5delTAAG, c.3010A>T (p.K1004(*)), c.853G>C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.(*)1376A>C, rs7238459; c.(*)1579G>A, rs559994; c.(*)1397A>G, rs150573037; c.(*)1631C>T, rs193227855; c.(*)1889G>C, rs149259359) were identified in the 3′UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype–phenotype correlations. Oxford University Press 2019-12-01 2019-10-10 /pmc/articles/PMC6969370/ /pubmed/31600781 http://dx.doi.org/10.1093/hmg/ddz239 Text en © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle General Article
Strafella, Claudia
Caputo, Valerio
Galota, Rosaria Maria
Campoli, Giulia
Bax, Cristina
Colantoni, Luca
Minozzi, Giulietta
Orsini, Chiara
Politano, Luisa
Tasca, Giorgio
Novelli, Giuseppe
Ricci, Enzo
Giardina, Emiliano
Cascella, Raffaella
The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title_full The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title_fullStr The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title_full_unstemmed The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title_short The variability of SMCHD1 gene in FSHD patients: evidence of new mutations
title_sort variability of smchd1 gene in fshd patients: evidence of new mutations
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969370/
https://www.ncbi.nlm.nih.gov/pubmed/31600781
http://dx.doi.org/10.1093/hmg/ddz239
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