Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review

Abstract

Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10-year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development.

Keywords: behavior characterization; epigenetic machinery; neurodevelopment; whole exome sequencing.

Figure 1. Dysmorphic facial and physical features of the patient

A. Facial features. B. Full-body photograph displays relative overweight. C. Sequencing depth and coverage captured through Whole Exome Sequencing. D. Schematic illustrating the domains of the HIST1H1E protein and mutations. Locations of previously-reported mutations are illustrated with green squares, while the patient presented in this case study is represented with a red circle. The epitope used for figures G and H is against the N-terminus of the protein, and targets amino acids 1 – 50. E. Nucleotide sequence for human HIST1H1E gene. The bold, red, underlined nucleotide illustrates the patient’s c.435dupC mutation. F. The normal amino acid sequence for HIST1H1E (top) has a C-terminus (black) largely composed of K, A, and P (underlined) residues. The predicted mutated amino acid sequence (bottom) is predicted to change at the insertion point (bold), drastically reducing the content of K, A, and P residues (underlined) found in the C-terminus (red). G. Western blot using whole-cell lysate from patient and control blood samples shows a reduction in HIST1H1E protein expression. H. Quantification of western blot examining HIST1H1E protein content.

Figure 2. Schematic illustrating the distribution of epigenetic regulator genes implicated in ASD, and the predicted mechanism of disruption within epigenetic regulation pathways

HIST1H1E is the first gene reported to be implicated in autism through interference with the basic machinery of epigenetic regulation.