Correlating Neuroimaging and CNVs Data: 7 Years of Cytogenomic Microarray Analysis on Patients Affected by Neurodevelopmental Disorders

Abstract

The aim of this study was to evaluate the relationship between neurodevelopmental disorders, brain anomalies, and copy number variations (CNVs) and to estimate the diagnostic potential of cytogenomical microarray analysis (CMA) in individuals neuroradiologically characterized with intellectual developmental disorders (IDDs) isolated or associated with autism spectrum disorders (ASDs) and epilepsy (EPI), all of which were identified as a "synaptopathies." We selected patients who received CMA and brain magnetic resonance imaging (MRI) over a 7-year period. We divided them into four subgroups: IDD, IDD + ASD, IDD + EPI, and IDD + ASD + EPI. The diagnostic threshold of CMA was 16%. The lowest detection rate for both CMA and brain anomalies was found in IDD + ASD, while MRI was significantly higher in IDD and IDD + EPI subgroups. CMA detection rate was significantly higher in patients with brain anomalies, so CMA may be even more appropriate in patients with pathological MRI, increasing the diagnostic value of the test. Conversely, positive CMA in IDD patients should require an MRI assessment, which is more often associated with brain anomalies. Posterior fossa anomalies, both isolated and associated with other brain anomalies, showed a significantly higher rate of CMA positive results and of pathogenic CNVs. In the next-generation sequencing era, our study confirms once again the relevant diagnostic output of CMA in patients with IDD, either isolated or associated with other comorbidities. Since more than half of the patients presented brain anomalies in this study, we propose that neuroimaging should be performed in such cases, particularly in the presence of genomic imbalances.

Keywords: autism spectrum disorders; brain anomalies; epilepsy; intellectual developmental disorders; synaptopathies.

Fig. 1

( A ) Classification of 217 CNVs identified in our cohort of patients based on the American College of Medical Genetics guidelines and the European Guidelines for constitutional cytogenomic analysis. ( B ) Classification of patients according to CMA results. ( C ) Microarray positive rate (CMA + ) in MRI+ and MRI− patients. ( D ) CMA+ in MRI+ (black bars) and MRI− (gray bars) patients belonging to each clinical subgroup. ASD, autism spectrum disorder; CMA, cytogenomical microarray analysis; CNVs, copy number variations; EPI, epilepsy; IDDs, intellectual developmental disorders; MRI, magnetic resonance imaging; VUS, variants of unknown/uncertain significance.

Fig. 2

( A ) Distribution of MRI +/− patients among the clinical subgroups. ( B ) Incidence of MRI +/− patients among those resulted positive to CMA in each clinical subgroup. ( C ) Distribution of cases with isolated or multiple brain anomalies among clinical subgroups. ASD, autism spectrum disorder; CMA, cytogenomical microarray analysis; CNVs, copy number variations; EPI, epilepsy; IDDs, intellectual developmental disorders; MRI, magnetic resonance imaging.

Fig. 3

( A ) CMA positive rate in patients with specific brain malformations (black bars) and relative control groups (gray bars; see Results for control group definition). ( B ) Rates of P/LP CNVs found in patients with specific brain malformations (black bars) and in relative control groups (gray bars). ( C ) Correlation between number of brain malformations and rate of P/LP CNVs (correlation coefficient: 0.9833). CMA, cytogenomical microarray analysis; CNVs, copy number variations; MRI, magnetic resonance imaging.