Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNVs in ID and ASD patients

PeerJ. 2019 Nov 15:7:e7979. doi: 10.7717/peerj.7979. eCollection 2019.


Background: Autism spectrum disorders (ASD) and intellectual disabilities (ID) are heterogeneous and complex developmental diseases with significant genetic backgrounds and overlaps of genetic susceptibility loci. Copy number variants (CNVs) are known to be frequent causes of these impairments. However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. This could be resolved by stratifying patients according to their clinical features.

Aim: First, we sought to assess the significance of particular clinical features for the detection of pathogenic CNVs in separate groups of ID and ASD patients and determine whether and how these groups differ from each other in the significance of these variables. Second, we aimed to create a statistical model showing how particular clinical features affect the probability of pathogenic CNV findings.

Method: We tested a cohort of 204 patients with ID (N = 90) and ASD (N = 114) for the presence of pathogenic CNVs. We stratified both groups according to their clinical features. Fisher's exact test was used to determine the significance of these variables for pathogenic CNV findings. Logistic regression was used to create a statistical model of pathogenic CNV findings.

Results: The frequency of pathogenic CNV was significantly higher in the ID group than in the ASD group: 18 (19.78%) versus 8 (7%) (p < 0.004). Microcephaly showed a significant association with pathogenic findings in ID patients (p < 0.01) according to Fisher's exact test, whereas epilepsy showed a significant association with pathogenic findings in ASD patients (p < 0.01). The probability of pathogenic CNV findings when epilepsy occurred in ASD patients was more than two times higher than if epilepsy co-occurred with ID (29.6%/14.0%). Facial dysmorphism was a significant variable for detecting pathogenic CNVs in both groups (ID p = 0.05, ASD p = 0.01). However, dysmorphism increased the probability of pathogenic CNV detection in the ID group nearly twofold compared to the ASD group (44.4%/23.7%). The presence of macrocephaly in the ASD group showed a 25% probability of pathogenic CNV findings by logistic regression, but this was insignificant according to Fisher's exact test. The probability of detecting pathogenic CNVs decreases up to 1% in the absence of dysmorphism, macrocephaly, and epilepsy in the ASD group.

Conclusion: Dysmorphism, microcephaly, and epilepsy increase the probability of pathogenic CNV findings in ID and ASD patients. The significance of each feature as a predictor for pathogenic CNV detection differs depending on whether the patient has only ASD or ID. The probability of pathogenic CNV findings without dysmorphism, macrocephaly, or epilepsy in ASD patients is low. Therefore the efficacy of CNV analysis is limited in these patients.

Keywords: ADHD; Autism spectrum disorders; CNV; Congenital malformations; Epilepsy; Facial dysmorphia; Growth defects; Intellectual disabilities; Macrocephaly; Microcephaly.

Grants and funding

The study was supported by following grants: Ministry of Health, Czech Republic—conceptual development of research organization (MH CZ—DRO FNOL 00098892), Internal Grant Agency of the Palacký University in Olomouc (IGA UP LF_2018_005, IGA_LF_2019_003), Technology Agency of the Czech Republic (TACR TE02000058), The National Center for Medical Genomics (NCMG LM2015091), National Programme of Sustainability (NPU LO1304) and European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.