Abstract While germline variants in histone protein-encoding genes are emerging as the pathogenic mutations underlying rare, Mendelian disorders characterized by a conserved phenotype of neurodevelopmental syndrome coupled with craniofacial abnormalities, a systematic assessment of all human genes encoding histone proteins has not been performed to predict novel disease-candidate genes. We first defined a comprehensive list of 89 histone-encoding genes. We then analyzed which are most likely to underlay this conserved phenotype when mutated based on their intolerance to either missense or loss-of-function variation and based on their tissue expression profile. Strikingly few genes were found to be both ubiquitously expressed and significantly constrained against missense (7.9, n?=?7) or loss-of-function (6.7, n?=?6) variation. Notably, most of those significantly constrained genes encode replication-independent, variant histone proteins (7/7 in the missense analysis, 5/6 in the loss-of-function analysis). Of the seven genes predicted to be disease-causing when germline missense variation is present, three (H2AFV, H2AFY, H2AFY2) are novel disease-candidate genes. Five of the six genes predicted to be disease-causing with an underlying germline loss-of-function variant are novel disease-candidate genes (H2AFY2, H2AFZ, H2AFY, H2AFV, H1F0). These findings may serve as a focused reference for future sequencing of patients with the conserved phenotype.
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