Overlapping pathogenic de novo CNVs in neurodevelopmental disorders and congenital anomalies impacting constraint genes regulating early development

Abstract Neurodevelopmental disorders (NDDs) and congenital anomalies (CAs) are a collection of rare disorders with complex etiology. In this study, we investigated the less understood genomic overlap of copy number variants (CNVs) in two large cohorts of NDD and CA patients to identify de novo CNVs and candidate genes associated to both NDD and CA phenotypes. We analyzed clinical microarray CNV data from 10,620 NDD and 3,176 CA cases annotated using Horizon platform of GenomeArc Analytics and then applied rigorous downstream analysis to evaluate overlapping genes from NDD and CA CNVs. Out of 154 patients (NDD and CA cases), we extracted genes from overlapping 217 pathogenic de novo CNVs (47.3% (80/169) of NDD and 64.6% (31/48) CA cases) and performed constraint gene analysis. 79 constraint genes (10.1% non-OMIM entries) were found to have significantly enriched genomic overlap within rare de novo pathogenic deletions (P-value = 0.01, OR = 1.58) and 45 constraint genes (13.3% non-OMIM entries) within rare de novo pathogenic duplications (P-value = 0.01, OR = 1.97). Analysis of spatiotemporal transcriptome demonstrated both pathogenic deletion and duplication genes to be highly expressed during the prenatal stage in human developmental brain (P-value = 4.95 X 10− 6). From the list of overlapping genes, EHMT1, an interesting known NDD gene encompassed de novo pathogenic CNVs from both NDD and CA patients, whereas FAM189A1, and FSTL5 are new candidate genes from non-OMIM entries. In summary, we have identified constraint overlapping genes from CNVs in NDD and CA patients that have the potential to play a vital role in common disease etiology.