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Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

A series of computer studies showing the effect of cyanide (CN) on the electrophysiology of cardiac tissue is presented. A mathematical model of the electrophysiology of cardiac tissue, with initial and boundary conditions based on experimental data from studies using CN as metabolic blockers from the literature, was used to simulate changes in the electrical activity of the heart. Emphasis was on the modulation of ion concentrations in the cells, changes in current magnitudes, and the activation of currents that are dormant under normal circumstances. These calculations showed for the first time: (1) disturbance of the energy homeostasis and ion concentrations in cardiac tissue due to CN results in the reversal of the direction from the normal and change in magnitudes of cellular membrane currents. These, in turn, change the morphology of the action potential and the electrocardiogram (ECG). This is the initial step leading to ventricular fibrillation, the usual endpoint in the effect of CN on the heart. (2) CN causes cell swelling and hemorrhaging in cardiac tissue. Cell swelling activates chloride membrane currents affecting homeostasis of the tissue. These effects were shown to be important for the electrical state of the CN-affected tissue and were included for the first time in a model of CN-affected cardiac tissue. (3) The calculations reproduced aspects of the changes in an ECG of a subject under the effect of a lethal dose of CN. (4) The obtained results suggest and define the characteristics required of a pharmacological intervention needed to overcome or reverse CN poisoning, of vital importance for development of therapeutics for force protection. Primarily, such intervention needs to reduce the calcium overload of the cardiac cell, restore the depolarizing sodium current, and alleviate the accumulation of potassium ions exterior to the cell., The original document contains color images.

The development of antidotes against cyanide (CN) poisoning for the protection of the warfighter is still hampered by a lack of detailed understanding of the modulation of CN-affected cellular processes. Advances in high-performance computer technology and algorithms now enable computational models of the cellular processes on the newest high performance scalable computers, for the first time, to furnish many of the sought-after answers and complement animal studies. A mathematical model of the electrophysiology of cardiac tissue with initial and boundary conditions based on experimental data from studies using CN as metabolic blockers from the literature, was used to simulate changes in the electrical activity of the heart due to the effect of the presence of CN. Emphasis was on the modulation of ion concentrations in the cells, changes in current magnitudes and the activation of currents that are dormant under normal circumstances., See also ADM001736, Proceedings for the Army Science Conference (24th) held in Orlando, FL on 29 Nov-2 Dec 2004. The onginal document contains color images. Prepared in collaboration with U.A. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD.