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Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies

BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical signifi...

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Autores principales: Maini, I., Ivanovski, I., Djuric, O., Caraffi, S. G., Errichiello, E., Marinelli, M., Franchi, F., Bizzarri, V., Rosato, S., Pollazzon, M., Gelmini, C., Malacarne, M., Fusco, C., Gargano, G., Bernasconi, S., Zuffardi, O., Garavelli, L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845186/
https://www.ncbi.nlm.nih.gov/pubmed/29523172
http://dx.doi.org/10.1186/s13052-018-0467-z
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author Maini, I.
Ivanovski, I.
Djuric, O.
Caraffi, S. G.
Errichiello, E.
Marinelli, M.
Franchi, F.
Bizzarri, V.
Rosato, S.
Pollazzon, M.
Gelmini, C.
Malacarne, M.
Fusco, C.
Gargano, G.
Bernasconi, S.
Zuffardi, O.
Garavelli, L.
author_facet Maini, I.
Ivanovski, I.
Djuric, O.
Caraffi, S. G.
Errichiello, E.
Marinelli, M.
Franchi, F.
Bizzarri, V.
Rosato, S.
Pollazzon, M.
Gelmini, C.
Malacarne, M.
Fusco, C.
Gargano, G.
Bernasconi, S.
Zuffardi, O.
Garavelli, L.
author_sort Maini, I.
collection PubMed
description BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. RESULTS: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. CONCLUSION: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13052-018-0467-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-58451862018-03-14 Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies Maini, I. Ivanovski, I. Djuric, O. Caraffi, S. G. Errichiello, E. Marinelli, M. Franchi, F. Bizzarri, V. Rosato, S. Pollazzon, M. Gelmini, C. Malacarne, M. Fusco, C. Gargano, G. Bernasconi, S. Zuffardi, O. Garavelli, L. Ital J Pediatr Research BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. RESULTS: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. CONCLUSION: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13052-018-0467-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-09 /pmc/articles/PMC5845186/ /pubmed/29523172 http://dx.doi.org/10.1186/s13052-018-0467-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Maini, I.
Ivanovski, I.
Djuric, O.
Caraffi, S. G.
Errichiello, E.
Marinelli, M.
Franchi, F.
Bizzarri, V.
Rosato, S.
Pollazzon, M.
Gelmini, C.
Malacarne, M.
Fusco, C.
Gargano, G.
Bernasconi, S.
Zuffardi, O.
Garavelli, L.
Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title_full Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title_fullStr Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title_full_unstemmed Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title_short Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
title_sort prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-cgh results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845186/
https://www.ncbi.nlm.nih.gov/pubmed/29523172
http://dx.doi.org/10.1186/s13052-018-0467-z
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