Genome-wide prediction of dominant and recessive neurodevelopmental disorder-associated genes

Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised machine learning framework (mantis-ml) to train inheritance-specific models for these disorders. The models have high predictive power (area under the receiver operator curves [AUCs]: 0.84-0.95), and the top-ranked genes were up to 2-fold (monoallelic models) and 6-fold (bi-allelic models) more enriched for high-confidence NDD risk genes compared to genic intolerance metrics alone. Additionally, genes ranking in the top decile were 45 to 180 times more likely to have literature support than those in the bottom decile. Collectively, this work provides robust NDD risk gene predictions that can complement large-scale gene discovery efforts and underscores the importance of considering inheritance in gene risk prediction.