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

Abstract

BackgroundSince 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.MethodWe 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.ResultsCopy 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.ConclusionOur work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.Electronic supplementary materialThe online version of this article (10.1186/s13052-018-0467-z) contains supplementary material, which is available to authorized users.

Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

“…; Maini et al . ). Two studies found an association with congenital heart diseases (Shoukier et al .…”

“…; Maini et al . ). Two studies pointed to hypotonia as a significant feature (Caballero Pérez et al .…”

“…; Maini et al . ). Two studies associated intrauterine growth retardation (IUGR) with pathogenic CNVs (D'Arrigo et al .…”

“…; Maini et al . ); and two showed an association with a family history of DD/ID (D'Arrigo et al . ; Caballero Pérez et al .…”

“…Eight previous studies, with different selection criteria, described specific clinical features that could favour the hypothesis of a GI in individuals with DD/ID (Shoukier et al 2013;Preiksaitiene et al 2014;Roselló et al 2014;Caramaschi et al 2014;D'Arrigo et al 2016;Cappuccio et al 2016;Caballero Pérez et al 2017;Maini et al 2018). However, the findings of these studies are heterogeneous.…”