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Italian Journal of Pediatrics
Published in: Italian Journal of Pediatrics 1/2018

Open Access 01-12-2018 | Research

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

Authors: I. Maini, I. Ivanovski, O. Djuric, S. G. Caraffi, E. Errichiello, M. Marinelli, F. Franchi, V. Bizzarri, S. Rosato, M. Pollazzon, C. Gelmini, M. Malacarne, C. Fusco, G. Gargano, S. Bernasconi, O. Zuffardi, L. Garavelli

Published in: Italian Journal of Pediatrics | Issue 1/2018

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Abstract

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.
Appendix
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Literature
1.
Rosenfeld JA, Patel A. Chromosomal microarrays: understanding genetics of neurodevelopmental disorders and congenital anomalies. J Pediatr Genet. 2017;6:42–50.PubMed
2.
Nevado J, Mergener R, Palomares-Bralo M, Souza KR, Vallespín E, Mena R, et al. New microdeletion and microduplication syndromes: a comprehensive review. Genet Mol Biol. 2014;37:210–9.CrossRefPubMed
3.
Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet. 2008;124:1–17.CrossRefPubMed
4.
Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.CrossRefPubMedPubMedCentral
5.
Chong WW, Lo IF, Lam ST, Wang CC, Luk HM, Leung TY, et al. Performance of chromosomal microarray for patients with intellectual disabilities/developmental delay, autism, and multiple congenital anomalies in a Chinese cohort. Mol Cytogenet. 2014;7:34.CrossRefPubMedPubMedCentral
6.
Riggs ER, Wain KE, Riethmaier D, Smith-Packard B, Faucett WA, Hoppman N, et al. Chromosomal microarray impacts clinical management. Clin Genet. 2014;85:147–53.CrossRefPubMed
7.
Nowakowska B. Clinical interpretation of copy number variants in the human genome. J Appl Genetics. 2017;58:449–57.CrossRef
8.
Palmer E, Speirs H, Taylor PJ, Mullan G, Turner G, Einfeld S, et al. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet A. 2014;164A:377–85.CrossRefPubMed
9.
Hehir-Kwa JY, Pfundt R, Veltman JA, de Leeuw N. Pathogenic or not? Assessing the clinical relevance of copy number variants. Clin Genet. 2013;84:415–21.CrossRefPubMed
10.
Gijsbers AC, Schoumans J, Ruivenkamp CA. Interpretation of array comparative genome hybridization data: a major challenge. Cytogenet Genome Res. 2011;135:222–7.CrossRefPubMed
11.
Torres F, Barbosa M, Maciel P. Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implication. J Med Genet. 2016;53:73–90.CrossRefPubMed
12.
13.
Coulter ME, Miller DT, Harris DJ, Hawley P, Picker J, Roberts AE, et al. Chromosmal microarray testing influences medical management. Genet Med. 2011;13:770–6.CrossRefPubMed
14.
Cappuccio G, Vitiello F, Casertano A, Fontana P, Genesio R, Bruzzese D, et al. New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants. Ital J Pediric. 2016;42:39.CrossRef
15.
16.
D'Arrigo S, Gavazzi F, Alfei E, Zuffardi O, Montomoli C, Corso B, et al. The diagnostic yield of Array comparative genomic hybridization is high regardless of severity of intellectual disability/developmental delay in children. J Child Neurol. 2016;31(6):691–9.CrossRefPubMed
17.
Preiksaitiene E, Molytė A, Kasnauskiene J, Ciuladaite Z, Utkus A, Patsalis PC, et al. Considering specific clinical features as evidence of pathogenic copy number variants. J Appl Genet. 2014;55:189–96.CrossRefPubMed
18.
Caramaschi E, Stanghellini I, Magini P, Giuffrida MG, Scullin S, Giuva T, et al. Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations: a multivariate analysis. Ital J Pediatr. 2014;40:39.CrossRefPubMedPubMedCentral
19.
Roselló M, Martínez F, Monfort S, Mayo S, Oltra S, Orellana C. Phenotype profiling of patients with intellectual disability and copy number variations. Eur J Paediatr Neurol. 2014;18:558–66.CrossRefPubMed
20.
Shoukier M, Klein N, Auber B, Wickert J, Schröder J, Zoll B, et al. Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants? Clin Genet. 2013;83:53–65.CrossRefPubMed
21.
22.
Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am J Hum Genet. 2009;84:524–33.CrossRefPubMedPubMedCentral
23.
24.
Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, et al. Genom sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7.CrossRefPubMed
25.
Beaudet AL. The utility of chromosomal microarray analysis in developmental and behavioral pediatrics. Child Dev. 2013;84:121–32.CrossRefPubMed
26.
Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–46.CrossRefPubMedPubMedCentral
27.
Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011;13(9):777–84.CrossRefPubMedPubMedCentral
28.
An Y, Duan W, Huang G, Chen X, Li L, Nie C, et al. Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population. BMC Med Genet. 2016;9:2.
29.
Vulto-van Silfhout AT, Hehir-Kwa JY, van Bon BW, Schuurs-Hoeijmakers JH, Meader S, et al. Clinical significance of de novo and inherited copy-number variation. Hum Mutat. 2013;34(12):1679–87.CrossRefPubMed
Metadata
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
Authors
I. Maini
I. Ivanovski
O. Djuric
S. G. Caraffi
E. Errichiello
M. Marinelli
F. Franchi
V. Bizzarri
S. Rosato
M. Pollazzon
C. Gelmini
M. Malacarne
C. Fusco
G. Gargano
S. Bernasconi
O. Zuffardi
L. Garavelli
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Italian Journal of Pediatrics / Issue 1/2018
Electronic ISSN: 1824-7288
DOI
https://doi.org/10.1186/s13052-018-0467-z

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