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Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Understanding genetic control of cell diversification is essential for establishing mechanisms controlling biological complexity. This study demonstrates that the a priori deposition of H3K27me3 associated with gene repression across diverse cell states provides a genome-wide metric that enriches for genes governing fundamental mechanisms underlying biological complexity in differentiation, morphogenesis, and disease. We use this metric in combination with more than 1 million genome-wide data sets from diverse omics platforms to identify cell type specific regulatory mechanisms underlying diverse organ systems from species across the animal kingdom. From this analysis, we identify and genetically validate multiple novel genes controlling heart development in diverse chordates including humans and the tunicate, Ciona robusta. This study demonstrates that the conservation of epigenetic regulatory logic provides an effective strategy for utilizing large, diverse genome-wide data to establish quantitative basic principles of cell states to infer cell-type specific mechanisms that underpin the complexity of biological systems. AUTHOR CONTRIBUTIONS WJS:Developed the computational basis for the study, performed data analysis and wrote the manuscript. ES: Assisted in experimental and computational design for the study, performed data analysis, carried out functional genetic studies in hPSCs and wrote the manuscript. JX: Assisted with computational analysis and developed web interactive interface. MA: Performed computational analysis on HF pathogenesis data GA: Performed computational analysis on HF pathogenesis data SS: Assisted the computational analysis on different single-cell data platforms. BB: Performed computational analysis on melanoma studies. YS: Performed computational analysis on Mouse Organogenesis Cell Atlas data. BV: Performed functional analysis on ciona and validated the findings GP: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation NJ: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation YW: Helped with computational analysis of epigenetic data MP: Assisted with analysis and interpretation of melanoma data AS: Carried out experiments involving melanoma analysis YC: Carried out experiments involving melanoma analysis PT: Supervised work on spatiotemporal transcriptomic profiling of mouse gastrulation LC: Performed functional analysis on ciona and validated the findings DS: Supervised work on analysis of HF pathogenesis data QN: Provided assistance to implement TRIAGE on single-cell data sets. MB and NJP: Supervised the project, raised funding, and wrote the manuscript.

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