Ninety-five percent of the 400 million people around the world living with rare diseases lack therapeutic options beyond palliative interventions. In part, this results from the fact that more than 60% of individuals cannot yet attain a definitive molecular diagnosis on genetic testing, leading to the rapid accumulation of genes and variants of uncertain significance for which evidence is not yet available to determine their pathogenicity. A second contributing factor pertains to the challenge of capturing the genotypic and phenotypic heterogeneity of individuals living with Mendelian syndromes in our model systems. Our limited ability to do this obfuscates the genes, pathways, and functional signatures on which these unique variants converge, which is a significant barrier on the path towards therapeutic repurposing and development. Through a patient-guided and highly collaborative approach, we sought to address these challenges in partnership with the global community of individuals living with histonopathies, syndromes caused by germline variants in histone-encoding genes. We integrated publicly-available data and patient information to gain insights into the pathogenic mechanism of this emerging class of neurodevelopmental disorders, first by leveraging large-scale data in ClinVar, DECIPHER, gnomAD, and GTEx; then through a genotype-phenotype analysis of individuals with Bryant-Li-Bhoj syndrome; and finally with a pan-histonopathy analysis that included all 192 individuals known to harbor a germline variant in histone-encoding genes. Through these efforts, we identified gaps that we then sought to address through the generation of the data-visualization tool NeuroTri2-VISDOT and a multiomic atlas of neurodevelopment. Finally, we extend the lessons we learned through these projects to three additional Mendelian neurogenetic syndromes caused by germline variants in TBCK, ATAD2B, and MAP2K4. In sum, this work demonstrates the invaluable insights and innovations that can only be obtained in the rare disease space through responsible partnerships with affected communities as well as collaborative data-sharing as we work together to provide evidence-based recommendations to individuals with a definitive molecular diagnosis and answers to individuals who do not yet have the ability to name their syndrome.