Authors :
Presenting Author: Wei-Liang Chen, MD – Children's National Hospital
Jean-Madeleine De Sainte Agathe, MD – Pitie-Salpetriere Hospital; Taryn Athey, MD – University of Alberta; antionietta Coppola, N/A – University of Naples Federico II; Peter Kannu, MD – University of Alberta; Boris Keren, MD – Pitie-Salpetriere Hospital; John Mantovani, MD – Mercy Hospital St. Louis; Halie May, GC – Columbia University; Esther Nibbeling, MD – Leiden University Medical Center, Leiden, the Netherlands; Liesl Rehbock, MD – Leiden University Medical Center, Leiden, the Netherlands; Gijs Santen, MD – Leiden University Medical Center, Leiden, the Netherlands; Shraddha Srinivasan, MD – Columbia University; Dora Steel, MD – University College London; Ingrid Scheffer, MD – University of Melbourne; Heather Mefford, MD, PhD – St. Jude Children's Research Hospital
Rationale:
Canonical histone proteins are the core particles of nucleosome, critical for DNA packing and DNA-dependent processes. The function of the nucleosome is mainly regulated via post-translational modification (PTM) of its histone proteins. Additionally, canonical histone proteins (H2A, H2B, H3 and H4) have functionally non-redundant isoforms, which also contribute to the temporally and spatially regulated gene expression during life cycle. Variants in the histone genes (such as H3 and H4) or in the genes important for PTM have been found in patients with neurodevelopmental and epilepsy disorder.
H2AC6 (
HIST1H2AC), encode H2A type 1-C isoform, was not previously associated with human disorder.
Methods:
Approval to share clinical and genetics information was received from local institutional review boards (IRBs) and IRB at University of Washington. All the individuals except one have clinical trio exome sequencing via clinical laboratories. M
issense variants of H2AC6 were modeled with Swiss-Model by JDS , using the following wild-type structures as templates: 5y0c, 6muo, 7a08. Stabilizing or destabilizing consequences were estimated using Dynamut2. Figures were made with Mol* .Results:
In this study, we reported a cohort of 10 individuals with similar neurodevelopmental phenotype, including developmental delay/intellectual disability, epilepsy, behavioral manifestation and cerebellar atrophy. Less frequent phenotypic feature such as non-specific dysmorphism, difference in head circumference, involuntary movement, cataract, hearing loss were also seen. Most variants were either at or close to the predicted ligand binding site and/or interaction interface (with other histones proteins or DNA molecule).
In Silico modeling suggests a functional alteration (precluding interaction with other histone proteins or interfering the ligandability) in some of these variants.
Conclusions:
Variants in H2AC6 are associated with neurodevelopmental spectrum disorder characterized by developmental delay, epilepsy, cerebellar atrophy and behavioral manifestation. Most of the variants are close to the important functional domains.Interestingly, none of these variants is on post-translational modification (PTM) sites. Variant on PTMs might not be viable during embryogenesis. In Silico modeling suggests functional alteration of the amino acid substitution resulted from some of the reported variants. This case series demonstrated a new disease entity associated with epilepsy caused by pathogenic variant in the revolutionary conserved H2AC6.
Funding: No funding