NeuroCNVscore: a tissue-specific framework to prioritise the pathogenicity of CNVs in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are associated with altered development of the brain especially in childhood. Copy number variants (CNVs) play a crucial role in the genetic aetiology of NDDs by disturbing gene expression directly at linear sequence or remotely at three-dimensional genome level in a tissue-specific manner. Despite the substantial increase in NDD studies employing whole-genome sequencing, there is no specific tool for prioritising the pathogenicity of CNVs in the context of NDDs.

Using an XGBoost classifier, we integrated 189 features that represent genomic sequences, gene information and functional/genomic segments for evaluating genome-wide CNVs in a neuro/brain-specific manner, to develop a new tool, neuroCNVscore. We used Human Phenotype Ontology to construct an independent NDD-related set.

Our neuroCNVscore framework (https://github.com/lxsbch/neuroCNVscore) achieved high predictive performance (precision recall=0.82; area under curve=0.85) and outperformed an existing reference method SVScore. Notably, the predicted pathogenic CNVs showed enrichment in known genes associated with autism.

NeuroCNVscore prioritises functional, deleterious and pathogenic CNVs in NDDs at whole genome-wide level, which is important for genetic studies and clinical genomic screening of NDDs as well as for providing novel biological insights into NDDs.