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Histones: coming of age in Mendelian genetic disorders
  1. Karen Knapp1,
  2. Nihar Naik1,
  3. Sankalita Ray1,
  4. Gijs van Haaften2,
  5. Louise S Bicknell1
  1. 1Department of Biochemistry, University of Otago, Dunedin, New Zealand
  2. 2Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  1. Correspondence to Dr Louise S Bicknell, Department of Biochemistry, University of Otago, Dunedin, 9016, New Zealand; louise.bicknell{at}


Histones hold significant interest in development and genetic disorders due to their critical roles in chromatin dynamics, influencing gene expression and genome integrity. These roles are linked to alterations of post-translational marks, which are generally concentrated in the histone tails. The machinery modifying or interpreting these marks, known as chromatin writers, erasers or readers, have been associated with many Mendelian disorders; however, it has been only recently that the histone proteins themselves have been directly implicated in Mendelian conditions. High throughput sequencing has recently identified mutations in genes encoding histone H1, H3 and H4, all causing neurodevelopmental disorders with clinical variability. Notably, many of the mutations lie outside of recognised post-translational modification-associated residues, suggesting disrupting the core functions of histones is a primary molecular mechanism underpinning these neurodevelopmental phenotypes. In this review, we describe the clinical and genetic features of histone-related disorders, focusing on the unique aspects associated with each histone gene family, while noting the commonalities which provide insight into the required roles for histone fidelity in brain development and functioning.

  • Genetics, Medical

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  • Contributors LSB and GvH developed the idea. LSB wrote the manuscript with the assistance of KK, NN, SR and GvH. KK prepared figures. All authors approved the final manuscript.

  • Funding KK, NN and LSB are supported by Marsden funding, administered by Royal Society Te Apārangi of New Zealand. SR is funded by Cure Kids. LSB was supported in the writing of this review by the University of Otago Health Services Division Women’s Writing Retreat.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.